Skip to main content

Cytomegalovirus infection may be oncoprotective against neoplasms of B-lymphocyte lineage: single-institution experience and survey of global evidence

Abstract

Background

Although cytomegalovirus (CMV) is not considered tumorigenic, there is evidence for its oncomodulatory effects and association with hematological neoplasms. Conversely, a number of experimental and clinical studies suggest its putative anti-tumour effect. We investigated the potential connection between chronic CMV infection in patients with B-lymphocyte (B-cell) malignancies in a retrospective single-center study and extracted relevant data on CMV prevalences and the incidences of B-cell cancers the world over.

Methods

In the clinical single-center study, prevalence of chronic CMV infection was compared between patients with B-cell leukemia/lymphoma and the healthy controls. Also, global data on CMV seroprevalences and the corresponding country-specific incidences of B- lineage neoplasms worldwide were investigated for potential correlations.

Results

Significantly higher CMV seropositivity was observed in control subjects than in patients with B-cell malignancies (p = 0.035). Moreover, an unexpected seroepidemiological evidence of highly significant inverse relationship between country-specific CMV prevalence and the annual incidence of B-cell neoplasms was noted across the populations worldwide (ρ = −0.625, p < 0.001).

Conclusions

We try to draw attention to an unreported interplay between CMV infection and B-cell lymphomagenesis in adults. A large-scale survey across > 70 countries disclosed a link between CMV and B-cell neoplasms. Our evidence hints at an antagonistic effect of chronic CMV infection against B-lymphoproliferation.

Background

Although a benign infectious agent in the healthy, the human cytomegalovirus (CMV) is a notorious driver of morbidity and mortality in hematological patients with failed immunocompetence [1]. Cytomegalovirus infection is the most significant viral complication of allogeneic hematopoietic cell transplantation (HCT) [2, 3]. The virus is highly pervasive, with a widely varying seroprevalence due to different demographic factors including socioeconomic status (SES) of populaces and communities [4,5,6].

While not regarded as a bona fide tumorigenic virus, CMV boasts an array of features that imply its oncogenic potential. The genome of CMV carries two anti-apoptotic genes, upregulates p53 [7] and augments anaplasia in cancer cells and/or tumor-associated cells [8,9,10]. Also, CMV may contribute to cancer formation via a “hit-and-run” mechanism, as well [11,12,13,14]. Aditionally, recent studies have identified congenital CMV infection as a risk for developing childhood hematologic malignancy [15, 16].

In contrast, clinical evidence that favors an anti-limphoproliferative effect of CMV, recently came from de Carvalho Batista Éboli et al. (2022). They verified liver pretransplant positivity for CMV as a protective factor for posttransplant lymphoproliferative disorder (PTLD) in pediatric patients [17]. A possible virus-vs-leukemia phenomenon has also been described [18], along with inhibition of migration of tumor cells [19, 20]. Several experiments done with murine CMV documented apoptosis in tumor cells [21, 22]. In humans, patients experiencing CMV reactivation early after allogeneic HCT for acute leukemia and non-Hodgkin lymphomas (NHL) have reduced relapse rates [23,24,25,26,27].

Research on CMV infection, reactivation, and multiorgan sequelae preferentially focuses on T-lymphocyte (T-cell) immune response. Recent studies on humanized animal models make the case in favor of importance of anti-CMV antibodies as being produced by host B-cells [28,29,30,31,32].

We asked if CMV seroststus may relate to a possible oncomodulatory role played by chronic CMV infection in individuals afflicted by lymphoid neoplasias derived from a single histologic lineage. The current work provides evidence that chronic CMV infection protects against malignant diseases of B-lymphocyte origin.

Methods

Patient and control cohorts

Our retrospective study cohort (N = 83; M/F = 43/40) was monocentric and comprised patients treated at the Clinic of Hematology, University Clinical Center, Belgrade, Republic of Serbia. The median age was 49.45 years (M = 52.3, range 20–73; F = 48.1, range 21–73). Information on demographic markers, underlying B-cell disorders, and chemoradiation regimens administered was abstracted from patients' medical records. Principal patient characteristics, diagnoses and chemotherapy regimens are presented in Tables 1 and 2. Close relatedness of malignant diseases with B-lymphocyte ontogeny was considered to have a virological authority over the clinical diversity of B-cell neoplasms.

Table 1 Principal demographics, clinical characteristics, and CMV serology of the patient group
Table 2 Details on chemotherapy

The control group (N = 259; M/F = 73/186) consisted of population-based pauci-symptomatic noninstitutionalized civilians (mean age: 41.79 years, range: 20–86). None among the controls has had a record of malignant disease. Study cohorts differed substantially by age and gender (p < 0.001) requiring statistical matching (Table 3).

Table 3 Statistical information on patient and control groups prior and after matching for age and gender

Sampling and data collection

Whole blood was a clinical source of samples collected between February and November 2017 by venipuncture using standardized clot-activator vacutainers. After clotting and centrifugation the serum fraction was screened for anti-CMV IgG and IgM antibodies at the Virology Laboratory of the Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade. Antibody classes were determined by means of commercial anti-CMV ELISA IgG and IgM kits (EUROIMMUN AG, Lübeck, Germany), with antibody detection performed spectrophotometrically on an ELISA Reader 270 (bioMérieux, Marcy-l’Étoile, France).

Peripheral blood samples from control cohort members were profiled for the presence of anti-CMV antibodies at the Institute of Virology, Vaccines, and Sera “Torlak”, Serbian National Reference Laboratory for Viruses. Commercial kits (Enzygnost, Marburg, Germany) and a Multiskan Ex ELISA Reader (Thermo Electron Corporation, Waltham, MA, USA) were used to detect IgG and IgM classes.

Prevalence of IgG seropositivity is a hallmark of past infections in a population [6]. Cytomegalovirus positivity was based on detection of either CMV specific IgG or both IgG and IgM in the serum indicating contact with the pathogen. All persons presenting with an antibody profile consistent with primoinfection were excluded from the study, as it was posited that there is not enough time for a B-cell malignancy to develop within a first-contact millieu.

Diseases herein studied belonged strictly to B-cell immunolymphoproliferative disorders. The diagnoses were established and morphologically code-specified according to the International Classification of the Diseases for Oncology by World Health Organization, ICD-0-3 [33] and the 2016 revision of the World Health Organization Classification of Lymphoid Neoplasms [34].

In order to compare our results with available data at a global level, we interrogated published information on CMV prevalences and burden of B-cell malignancies across the globe. The PubMed advanced search was used with the search keywords "cytomegalovirus", "CMV", "B lymphoma", "Hodgkin’s disease", "non-Hodgkin lymphoma", "B acute lymphoblastic leukemia", "B chronic lymphocytic leukemia" and "myeloma", all being neoplasms of the B-cell lineage.

Incidences of B-cell malignancies were obtained from the World Health Organization Global Cancer Observatory (GLOBOCAN) [35] and compared to CMV prevalences from 74 countries for which this data was available [36]. Age-adjusted annual incidence rates (/105 population) of B-cell neoplasms (standardized to the year 2000 US Census Bureau million population by the direct method) were collected and presented as sums rather than separately and apart.

It is important to note that published reports do not always clearly discriminate between B-cell and T-cell disorders. Cases of B- and T-acute lymphoblastic leukemia (B-ALL and T-ALL) were frequently presented jointly as “ALL”. B- and T-non-Hodgkin's lymphoma (B-NHL and T-NHL) were often jointly described as “NHL”. Moreover, even if B- and T-cell components of lymphoproliferative diseases were reported, complementary information on the prevalence of CMV seropositivity for each component was often not reported. Crude annual incidence rates (/105) of all B-cytopathies were summed-up in Tables 4 and 5. Merging the rates enhanced their statistical power and ease of interpretation.

Table 4 Provisional data on CMV seropositivity in summarized incidence rates of B-lymphoid neoplasms around the world
Table 5 Crude incidence rate estimates of key B-cell malignancies: aggregate rates by country, race, and ethnicity

Clinical sampling was approved by University Clinical Centre of Serbia, University of Belgrade Ethical Review Board. The patients signed individually a document of informed consent.

Statistical analysis

Results are presented as count (percent) or median (min–max) depending on data type. Groups were compared using non-parametric tests, Fisher's exact test for frequencies, Mantel–Haenszel chi square test for trend and Mann–Whitney U test for numeric data with non-normal distribution. Propensity score matching was performed in order to find the best matching cases in control group by age and gender. Correlation between numerical variables was performed using Spearman correlation analysis. All p-values less than 0.05 were considered significant. All data were analyzed using SPSS 20.0 (IBM corp.) statistical software.

Results

General characteristics of the patient group are presented in Tables 1 and 2 and the comparisons between the study and control groups is presented in Table 3. Tests for IgG antibodies were successful in all patients.

CMV serostatus was relatively homogeneous across different B-cell neoplasms despite their glaring clinical diversity which ranged from acute B-ALL and aggressive B-NHL to mature B-chronic lymphocytic leukemia (B-CLL), low-grade B-NHL, and plasmocytoma (Table 1). Biological characteristics they share in common (immunophenotype and somatic mutation profiles) remain preserved in cancerogenesis such that clinical distinctiveness of B-cell neoplasms did not hamper the understanding of their virology.

Most IgG positives were patients with NHL (33/35, 94.3%) followed by B-CLL (8/9, 88.9%), and Hodgkin's disease (HD) (13/17, 76.5%). CMV was least pervasive in multiple myeloma (2/3, 66.7%) but the patients were too few. Low natural incidence of some B-cell disorders resulted in a low number of consecutive patients detected over a short interval of observation. All patients with hairy cell leukemia (2/2), Waldenström's macroglobulinemia (2/2), and non-specified B-cell lymphoma (2/2) were IgG positive. Their numbers were insufficient and were excluded from separate analyses. Positive CMV serology did not correlate among different B-lymphoproliferative diseases (p = 0.339).

The study cohorts had markedly different (p < 0.001) age and gender structure (Table 3). This required statistical matching to compensate for these discrepancies, after which there remained statistical variance for neither of variables (Table 3). Interestingly, a notable difference in CMV seropositivity emerged between the study group and normal populace after the gender/age matching was performed. The prevalence of CMV infection was significantly higher in the control group (p = 0.035), compared to the patient group (Table 3).

Binary logistic regression with B-cell malignancy as dependent and CMV serostatus as independent variable demonstrated that subjects with positive serostatus were ~ 7 times less likely (OR, 0.067; 95% CI, 0.016 to 1.150) to have a B-cell malignancy relative to seronegatives. The difference was not significant (p = 0.067), but near the conventional level of significance (0.05).

The results pointed to a potential protective effect that CMV may proffer against B-cell dyscrasia. In order to investigate our evidence on a much larger scale, we compared annual incidence rates of B-cell neoplasms to CMV prevalences in 74 countries for which these variables were available (Fig. 1A–D). Interestingly, a significant negative correlation between CMV pervasiveness and the incidence of all clinical types of B-cell malignancies was observed the world over (Fig. 1A; Spearman ρ = −0.625, p < 0.001). Similarly, an inverse association was evidenced separately for three different B-cell malignancies: HD (Fig. 1B; Spearman ρ = −0.618, p < 0.001), non-Hodgkin lymphomas (Fig. 1C; Spearman ρ = −0.617, p < 0.001), and myeloma (Fig. 1D; Spearman ρ = −0.633, p < 0.001), separately.

Fig. 1
figure 1

The scatter charts present country specific CMV prevalence (mean) plotted against estimated age-standardized (world) annual incidence rates (per 100,000) of microscopically verified cases of B-cell types of cancer in 74 countries (blue circles) [35, 36, 69]. A) B-cell malignancies (all types) (Spearman ρ = -0.625, p < 0.001), B) Hodgkin’s disease (Spearman ρ = -0.618, p < 0.001), C) non-Hodgkin lymphomas (Spearman ρ =  = -0.617, p < 0.001), and D) multiple myeloma (Spearman ρ = -0.633, p < 0.001) in 2020. The inverse relationship between viral pervasiveness and the annual incidence rate of hematologic malignancies is highly significant for all (A) and each individual B-cell cancer type (C-D)

These results support the reality of oncoprotection by the chronic CMV infection against B-lymphomagenesis irrespective of a clinical form of a B-cell neoplasm.

Discussion

This is the first study reporting on the current estimate of CMV infection in Serbian hemato-oncological patients and healthy controls. Also, our clinical results are supported by the worldwide survey of relevant data. Together, they offer the first insight into a possible connection between the chronic CMV infection and B-cell neoplasms, hinting at an oncoprotection conferred by this virus on its host.

CMV seroprevalences in patients with hematological malignancies

CMV seroprevalence varies in published studies on patients with hematological malignancies. Virus prevalence in our patient cohort (90.4%) places the Republic of Serbia among the most CMV-permeated populations in the world [37,38,39,40,41,42,43,44]. Much lower seroprevalence (70%) of anti-CMV IgG was reported in a multicenter cohort of Swedish patients (Re: Mission, NCT01347996, www.clinicaltrials.gov [45]. The lowest CMV infestation was reported in landmark studies from the US [46, 47], a highly developed country with one of the largest incidence rates of B-cell disorders.

In studies on HCT recipients [3], and B-CLL patients [48], females were significantly more CMV seropositive. Similar to our clinical population, in Brazilian patients with various hematologic disorders females were more CMV seropositive than males albeit not significantly [37]. On the contrary, Sudan females with leukemia were less seropositive for CMV than males [49]. Marchesi et al. [39] reported largest prevalence of CMV in patients with B-CLL, and multiple myeloma which is similar to the present findings.

Inverse association between CMV seroprevalence and incidence of B-cell neoplasms across the globe

There is a stark difference in annual incidences of B-lymphoid malignancies between Western and Eastern countries [50, 51]. We try to draw attention to an inverse association between the annual age-adjusted incidences of B-cell malignancies and the spread of CMV seropositivity at a global level (Tables 5 and 6, Fig. 1A–D). Seroprevalence in presumably epidemiologically unrelated communities was frequently lower in patients with B-cell and even in other malignancies (acute myeloid leukemia, AML; chronic myeloid leukemia—CML) than that reported in voluntary blood/organ donors and in the general population [36]. This difference is explainable if chronic CMV infection conferred a degree of protection on its immunocompetent host against B-cell malignancies. This is consistent with the evidence in the current work where healthy controls were significantly more CMV seropositive (p = 0.035; Table 3) than patients with B-cell malignancies. A potential explanation might be an increase in resistence against B-cell neoplasia fostered by primary CMV infection.

Table 6 Country-specific CMV seroprevalence in patient cohorts compared to matched blood/organ donors and healthy general populations

As the prevalence of CMV infection recedes across the populations, corresponding annual incidence of B-cell diseases tends to increase. For decades, incidence of lymphoid neoplasms has been globally increasing across age strata and sex. This may signify a gradual loss of protection provided by the latent CMV infection which is being globally eroded by steadily improving economic prowess and modern access to health care.

A racial/ethnic background is related to SES [52, 53]. The difference in incidence of B-lymphoid malignancies between the US and Japan is elevated, 2.5- to fivefold. The largest proportional difference between the US and Japan was in B-CLL (the US, 24.1%; Japan, 3.2%) [52]. Annual incidence rates of B-cell neoplasms in the US-born Asians/Pacific islanders are generally intermediate to those in the US whites and East Asians; exactly parallel trend is observed in their respective CMV seroprevalences. The incidence rates of B-cell neoplasms tend to negatively parallel the prevalence of CMV seropositivity in respective populations worldwide (Fig. 1A‒D). HD and B-NHL showed the largest difference in annual incidences between the US and East Asian countries. The SES correlates with trends in age-standardized incidences of B-lymphoid disorders and is also associated with CMV infection around the world. Seroprevalence of CMV decreased in pregnant women in Ishikawa Prefecture (Japan) from 93.2% to 66.7% over the period between 1980 and 1998 and in parallel with the increase in SES [54]. Of note, age-adjusted incidence of lymphoid malignancies in Japan increased significantly as opposed to no significant annual percent change in the US (Japan, + 2.4%; US, + 0.1%) [55]. This may be a consequence of growing SES in Japan and the consequent drop in CMV infection there.

Global disease burden reports [36, 52, 53, 55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72] suggest a significant inverse correlation between overall estimates of CMV seropositivity and the age-standardized and population-based incidence rate of B-cell cancers (Tables 4 and 6, Fig. 1A–D). Cytomegalovirus infection decreases as contemporary economy improves and affluence is gained across societal strata. Reduced rates of CMV primoinfection in developed countries may be the cause of an increased risk of contracting a B-cell malignancy. By contrast, high CMV prevalence in countries with adverse economic conditions, appears to mitigate the risk of B-lymphoproliferative disease. In populations where the prevalence of CMV declines an oncoprotective effect of CMV subsides such that an increased annual incidence rate of B-cell cancer is observed worldwide (Spearman ρ = -0.625, p < 0.001). However, some other factor(s) may operate along with CMV infection influencing the global correlation between increasing incidence of B-cell malignancies, improving SES, and reduced country-specific prevalence of CMV infection.

Clinical and in vitro experimental evidence supporting oncoprotection by CMV

Cytomegalovirus seroprevalence was higher in the controls than in our patients with B-cell malignancies (Table 3; p = 0.035). This argues against the promotive contribution of CMV in B-cell lymphomagenesis.

Evidence in favor of viral repression of the transformation process in cancer cells has been reported [73]. CMV inhibits the migratory capacity of mesenchymal breast cancer cell lines MDA-MB-231 and SUM1315 [19]. Mice xenografted with CMV-infected HepG2 cells were reported to manifest limited to no tumor growth, as opposed to an unbridled tumor expansion in placebo-treated mice [74]. A runaway tumor growth was inhibited by restricting STAT3 activation, as well as by activation of the intrinsic apoptotic pathway [74, 75]. Apoptosis was also registered in the lung tissue of xeno-engrafted mice where HepG2 cells infected with human CMV were administered subcutaneously [74]. Erlach et al. [21, 22] proposed an innate anti-tumor mechanism elicited by murine CMV infection involving apoptosis of a liver-adapted clonal variant of B-cell lymphoma. The murine CMV infection had a highly suppressive effect on lymphoma cells even without infecting them, resulting in a significant survival benefit. Erkes et al. [76] also demonstrated clearance of tumors in a mouse melanoma model after CMV was inoculated into growing neoplasm. Also, an inhibiting effect of CMV glycoprotein B on breast cancer cell migration was recently documented by Yang et al.[20].

Anti-tumor effects of CMV infection were tentatively supported by reports of reduced relapse rates in patients with CMV reactivation early after allogeneic HCT for acute leukemia and NHL [23,24,25,26,27]. Changes within the immune system caused by CMV suggest a possible virus-vs-leukemia phenomenon [18] analogous to graft-vs-leukemia effect in B-CLL [77].

A study which screened neonatal Guthrie blood spots for CMV did not find that the CMV positives contracted B-ALL more often later in life [78]. MacKenzie et al. have screened common ALL patients and controls for presence of various herpesviruses, but were in doubt that a herpesvirus is an etiological agent in B-ALL [79]. Another study analyzed herpesvirus DNA in Guthrie cards and found no trace of EBV or HHV-6 but CMV presence has not been assessed [80]. Evidence garnered from these studies substantiates the assumption that CMV may forestall initiation of B-cell neoplasms.

A major strength of the present exploration is the use of a nationally representative sample to estimate CMV seroprevalence in the Republic of Serbia. Noteworthy limitations of our work are its retrospective nature and an artefact from a small sample size. Furthermore, a passive take of donor's IgG antibodies cannot be entirely excluded. This drawback to the study was mitigated by lower CMV seropositivity among blood transfusion-treated patients as compared to healthy controls.

Conclusions

Conclusively, we present first set of data on CMV seroprevalence based on a sample of B-cell derived malignancies in Serbia. Also, we provide evidence that prevalences of CMV are strongly inversely associated with the annual incidence rates of malignant B-cell disorders the world over. This is suggestive of a possible protective effect of CMV against the profligate B-cell growth. The cellular niche may be less favourable for initiation of B-lymphomagenesis in chronic carriers of CMV. Prospective work with a larger study size of cell lineage-specific patient cohorts across clinical and histological lymphoma subtypes may be helpful in clarifying dilemmas regarding anti/pro tumoral activity of CMV.

Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available due to safeguarding patient anonymity, but are available from the corresponding author on reasonable request.

Abbreviations

AA:

Aplastic anemia

AL:

Acute leukemia

ALL:

Acute lymphoblastic leukemia

Allo-HCT:

Allogeneic hematopoietic cell transplantation

AML:

Acute myeloid leukemia

Auto-HCT:

Autologous hematopoietic cell transplantation

BMT:

Bone marrow transplant

CIBMTR:

Center for International Bone Marrow Transplant Research

CLL:

Chronic lymphocytic leukemia

CML:

Chronic myeloid leukemia

CMV:

Cytomegalovirus

GLOBOCAN:

Global Cancer Observatory

GVHD:

Graft-vs-host disease

HCT:

Hematopoietic cell transplantation

HD:

Hodgkin's disease

IARC:

International Agency for Research on Cancer

LY:

Lymphoid neoplasms

MDS:

Myelodysplastic syndrome

MENA:

Middle East North Africa

MM:

Multiple myeloma

MPN:

Myeloproliferative neoplasm

MRD:

Matched related donor

MUD:

Matched unrelated donor

n.m.:

Not mentioned

N/A:

Not applicable

NHL:

Non-Hodgkin lymphoma

PB-HCT:

Peripheral blood HCT

PCM:

Plasma cell myeloma

PTLD:

Posttransplant lymphoproliferative disorder

RIC:

Reduced intensity chemotherapy

SEER:

Surveillance, Epidemiology, and End Results

SES:

Socioeconomic status

ST:

Solid tumors

UCBT:

Umbilical cord blood transplantation

URD:

Unrelated donor

WD:

Waldenström's disease

References

  1. Piukovics K, Terhes G, Gurbity-Pálfi T, Bereczki Á, Rárosi F, Deák J, et al. Cytomegalovirus infection in patients with haematological diseases and after autologous stem cell transplantation as consolidation: a single-centre study. Ann Hematol. 2017;96:125–31. https://doi.org/10.1007/s00277-016-2831-7.

    Article  CAS  PubMed  Google Scholar 

  2. Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C. Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood. 2003;102(13):4255–60. https://doi.org/10.1182/blood-2002-10-3263.

    Article  CAS  PubMed  Google Scholar 

  3. Ljungman P, Brand R. Factors influencing cytomegalovirus seropositivity in stem cell transplant patients and donors. Haematologica. 2007;92:1139–42. https://doi.org/10.3324/haematol.11061.

    Article  PubMed  Google Scholar 

  4. Lachmann R, Loenenbach A, Waterboer T, Brenner N, Pawlita M, Michel A, et al. Cytomegalovirus (CMV) seroprevalence in the adult population of Germany. PLoS ONE. 2018;13(7):e0200267. https://doi.org/10.1371/journal.pone.0200267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20:202–13. https://doi.org/10.1002/rmv.655.

    Article  PubMed  Google Scholar 

  6. Marshall GS, Rabalais GP, Stewart JA, Dobbins JG. Cytomegalovirus seroprevalence in women bearing children in Jefferson County. Kentucky Am J Med Sci. 1993;305:292–6. https://doi.org/10.1097/00000441-199305000-00005.

    Article  CAS  PubMed  Google Scholar 

  7. Cheeran MC-J, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev. 2009;22(1):99–126. https://doi.org/10.1128/CMR.00023-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Michaelis M, Doerr HW, Cinatl J. The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia. 2009;11(1):1–9. https://doi.org/10.1593/neo.81178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cinatl J Jr, Cinatl J, Vogel JU, Rabenau H, Kornhuber B, Doerr HW. Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells. Intervirology. 1996;39(4):259–69. https://doi.org/10.1159/000150527.

    Article  PubMed  Google Scholar 

  10. Cinatl J, Vogel JU, Cinatl J, et al. Long-term productive human cytomegalovirus infection of a human neuroblastoma cell line. Int J Cancer. 1996;65:90–6. https://doi.org/10.1002/(SICI)1097-0215(19960103)65:1%3c90:AID-IJC16%3e3.0.CO;2-M.

    Article  PubMed  Google Scholar 

  11. Nelson JA, Fleckenstein B, Jahn G, et al. Structure of the transforming region of human cytomegalovirus AD169. J Virol. 1984;49:109–15. https://doi.org/10.1128/JVI.49.1.109-115.1984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Boldogh I, Huang ES, Rady P, et al. Alteration in the coding potential and expression of H-ras in human cytomegalovirus–transformed cells. Intervirology. 1994;37:321–9. https://doi.org/10.1159/000150396.

    Article  CAS  PubMed  Google Scholar 

  13. Shen Y, Zhu H, Shenk T. Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate “hit-and-run” oncogenic transformation in cooperation with the adenovirus E1A proteins. Proc Natl Acad Sci USA. 1997;94:3341–5. https://doi.org/10.1073/pnas.94.7.3341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Doniger J, Muralidhar S, Rosenthal LJ. Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate. Clin Microbiol Rev. 1999;12(3):367–82 (PMID: 10398670).

    Article  CAS  Google Scholar 

  15. Francis SS, Wallace AD, Wendt GA, et al. In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia. Blood. 2017;129:1680–4. https://doi.org/10.1182/blood-2016-07-723148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wiemels JL, Talbäck M, Francis S, Feychting M. Early infection with cytomegalovirus and risk of childhood hematologic malignancies. Cancer Epidemiol Biomarkers Prev. 2019;28(6):1024–7. https://doi.org/10.1158/1055-9965.EPI-19-0044.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Éboli LPDCB, Tannuri ACA, Tannuri U. Seropositivity for cytomegalovirus and PCR-EBV monitoring: Protective factors for posttransplant lymphoproliferative disorder in pediatric liver transplant. Pediatr Transplant. 2022;2022:e14226. https://doi.org/10.1111/petr.14226.

    Article  CAS  Google Scholar 

  18. Koldehoff M, Lindemann M, Opalka B, et al. Cytomegalovirus induces apoptosis in acute leukemia cells as a virus-versus-leukemia function. Leuk Lymphoma. 2015;56:3189–97. https://doi.org/10.3109/10428194.2015.1032968.

    Article  CAS  PubMed  Google Scholar 

  19. Oberstein A, Shenk T. Cellular responses to human cytomegalovirus infection: Induction of a mesenchymal-to-epithelial transition (MET) phenotype. Proc Natl Acad Sci USA. 2017;114:E8244–53. https://doi.org/10.1073/pnas.1710799114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang R, Liang J, Xu GX, et al. Human cytomegalovirus glycoprotein B inhibits migration of breast cancer MDA-MB-231 cells and impairs TGF-β/Smad2/3 expression. Oncol Lett. 2018;15(5):7730–8. https://doi.org/10.3892/ol.2018.8344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Erlach KC, Böhm V, Seckert CK, et al. Lymphoma cell apoptosis in the liver induced by distant murine cytomegalovirus infection. J Virol. 2006;80:4801–19. https://doi.org/10.1128/JVI.80.10.4801-4819.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Erlach KC, Podlech J, Rojan A, Reddehase MJ. Tumor control in a model of bone marrow transplantation and acute liver-infiltrating B-cell lymphoma: an unpredicted novel function of cytomegalovirus. J Virol. 2002;76:2857–70. https://doi.org/10.1128/jvi.76.6.2857-2870.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Elmaagacli AH, Steckel NK, Koldehoff M, et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood. 2011;118:1402–12. https://doi.org/10.1182/blood-2010-08-304121.

    Article  CAS  PubMed  Google Scholar 

  24. Green ML, Leisenring WM, Xie H, et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood. 2013;122:1316–24. https://doi.org/10.1182/blood-2013-02-487074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Koldehoff M, Ross SR, Dührsen U, et al. Early CMV-replication after allogeneic stem cell transplantation is associated with a reduced relapse risk in lymphoma. Leuk Lymphoma. 2017;58:822–33. https://doi.org/10.1080/10428194.2016.1217524 (PMID: 27687578).

    Article  CAS  PubMed  Google Scholar 

  26. Inagaki J, Noguchi M, Kurauchi K, et al. Effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic stem cell transplantation in pediatric acute leukemia. Biol Blood Marrow Transplant. 2016;22:300–6. https://doi.org/10.1016/j.bbmt.2015.09.006.

    Article  PubMed  Google Scholar 

  27. Litjens NHR, van der Wagen L, Kuball J, Kwekkeboom J. Potential beneficial effects of cytomegalovirus infection after transplantation. Front Immunol. 2018;9:389. https://doi.org/10.3389/fimmu.2018.00389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lilleri D, Gerna G, Furione M, Zavattoni M, Spinillo A. Neutralizing and ELISA IgG antibodies to human cytomegalovirus glycoprotein complexes may help date the onset of primary infection in pregnancy. J Clin Virol. 2016;81:16–24. https://doi.org/10.1016/j.jcv.2016.05.007.

    Article  CAS  PubMed  Google Scholar 

  29. Theobald SJ, Khailaie S, Meyer-Herman M, Volk V, Olbrich H, Danisch S. Signatures of T and B cell development, functional responses and PD-1 upregulation after HCMV latent infection and reactivations in Nod.Rag.Gamma Mice humanized with cord blood CD34+ cells. Front Immunol. 2018;9:2734. https://doi.org/10.3389/fimmu.2018.02734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Martins JP, Andoniou CE, Fleming P, Kuns RD, Schuster IS, Voigt V, et al. Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation. Science. 2019;363(6424):288–93. https://doi.org/10.1126/science.aat0066.

    Article  CAS  PubMed  Google Scholar 

  31. Gerna G, Lilleri D. Human cytomegalovirus (HCMV) infection/re-infection: development of a protective HCMV vaccine. New Microbiol. 2019;42(1):1–20 (PMID: 30671581).

    CAS  PubMed  Google Scholar 

  32. Theobald SJ, Kreer C, Khailaie S, Bonifacius A, Eiz-Vesper B, Figueiredo C, et al. Repertoire characterization and validation of gB-specific human IgG3 directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV. PLoS Pathog. 2020;16(7):e1008560. https://doi.org/10.1371/journal.ppat.1008560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fritz A, Percy C, Jack A, et al editors. International classification of diseases for oncology. 3rd ed. Malta: World Health Organization; 2013.

    Google Scholar 

  34. Swerdlow SH, Campo E, Pilleri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organizartion classification of lymphoid neoplasms. Blood. 2016;127:2375–90. https://doi.org/10.1182/blood-2016-01-643569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. https://gco.iarc.fr/

  36. Zuhair M, Smit GSA, Wallis G, Jabbar F, Smith C, Devleesschauwer B, et al. Estimation of the worldwide seroprevalence of cytomegalovirus: a systematic review and meta-analysis. Rev Med Virol. 2019;29(3):e2034. https://doi.org/10.1002/rmv.2034.

    Article  PubMed  Google Scholar 

  37. De Matos SB, Meyer R, Lima FW. Seroprevalence and serum profile of cytomegalovirus infection among patients with hematologic disorders in Bahia State. Brazil J Med Virol. 2011;83:298–304. https://doi.org/10.1002/jmv.21965.

    Article  PubMed  Google Scholar 

  38. Ng AP, Worth L, Chen L, Seymour JF, Prince HM, Slavin M, et al. Cytomegalovirus DNAemia and disease: incidence, natural history and management in settings other than allogeneic stem cell transplantation. Haematologica. 2005;90(12):1672–9 (PMID: 16330442).

    CAS  PubMed  Google Scholar 

  39. Marchesi F, Pimpinelli F, Gumenyuk S, Renzi D, Palombi F, Pisani F, et al. Cytomegalovirus reactivation after autologous stem cell transplantation in myeloma and lymphoma patients: a single-center study. World J Transplant. 2015;5:129–36. https://doi.org/10.5500/wjt.v5.i3.129.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Capria S, Gentile G, Capobianchi A, Cardarelli L, Gianfelici V, Trisolini SM, et al. Prospective cytomegalovirus monitoring during first-line chemotherapy in patients with acute myeloid leukemia. J Med Virol. 2010;82(7):1201–7. https://doi.org/10.1002/jmv.21779.

    Article  CAS  PubMed  Google Scholar 

  41. Zaidi ARZ, Al-Ammari MO, Al-Naamani M, Altaf SY, AlShehry N, Tailor IK, et al. Very high seroprevalence of cmv and ebv among a large series of patients with hematological malignancies at a tertiary care center in Saudi Arabia—a case for investigating cooperativity of viruses in carcinogenesis? Blood. 2019;134(Suppl 1):5818. https://doi.org/10.1182/blood-2019-131323.

    Article  Google Scholar 

  42. Xuan L, Huang F, Fan Z, Zhou H, Zhang X, Yu G, et al. Effects of intensified conditioning on Epstein-Barr virus and cytomegalovirus infections in allogeneic hematopoietic stem cell transplantation for hematological malignancies. J Hematol Oncol. 2012;5:46. https://doi.org/10.1186/1756-8722-5-46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu Y-C, Lu P-L, Hsiao H-H, Chang C-S, Liu T-C, Yang W-C, et al. Cytomegalovirus infection and disease after allogeneic hematopoietic stem cell transplantation: experience in a center with a high seroprevalence of both CMV and hepatitis B virus. Ann Hematol. 2012;91:587–95. https://doi.org/10.1007/s00277-011-1351-8.

    Article  CAS  PubMed  Google Scholar 

  44. Tomonari A, Takahashi S, Ooi J, Tsukada N, Konuma T, Kato S, et al. Imapact of cytomgalovirus serostatus on outcome of unrelated cord blood transplantation for adults: a single-institute experience in Japan. Eur J Haematol. 2008;80(3):251–7. https://doi.org/10.1111/j.1600-0609.2007.01006.x.

    Article  PubMed  Google Scholar 

  45. Bernson E, Hallner A, Sander FE, Nicklasson M, Nilsson MS, Christenson K, et al. Cytomegalovirus serostatus affects autoreactive NK cells and outcomes of IL2-based immunotherapy in acute myeloid leukemia. Cancer Immunol Res. 2018;6:1110–9. https://doi.org/10.1158/2326-6066.CIR-17-0711.

    Article  CAS  PubMed  Google Scholar 

  46. Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98:2043–51. https://doi.org/10.1182/blood.V98.7.2043.

    Article  CAS  PubMed  Google Scholar 

  47. Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis. 2002;185:273–82. https://doi.org/10.1086/338624.

    Article  PubMed  Google Scholar 

  48. Pourgheysari B, Bruton R, Parry H, Billingham L, Fegan C, Murray J, et al. The number of cytomegalovirus-specific CD4+ T cells is markedly expanded in patients with B-cell chronic lymphocytic leukemia and determines the total CD4+ T-cell repertoire. Blood. 2010;116:2968–74. https://doi.org/10.1182/blood-2009-12-257147.

    Article  CAS  PubMed  Google Scholar 

  49. Dafalla ABY, Elnil YFH, Gorish BMT. Seroprevalence of cytomegalovirus infection among leukemic patients in Khartoum state. Virol Mycol. 2018;7:2. https://doi.org/10.4172/2161-0517.1000183.

    Article  Google Scholar 

  50. Torres HA, Kontoyannis DP, Aguilera EA, Younes A, Luna MA, Tarrand JJ, et al. Cytomegalovirus infection in patients with lymphoma: An important cause of morbidity and mortality. Clin Lymphoma Myeloma. 2006;6(5):393–8. https://doi.org/10.3816/CLM.2006.n.016.

    Article  PubMed  Google Scholar 

  51. Armitage JO, Gascoyne RD, Lunning MA, Cavalli F. Non-Hodgkin lymphoma. Lancet. 2017;390(10091):298–310. https://doi.org/10.1016/S0140-6736(16)32407-2.

    Article  PubMed  Google Scholar 

  52. Clarke CA, Glaser SL, Gomez SI, Wang SS, Keegan TH, Yang J, et al. Lymphoid malignancies in US Asians: incidence rate differences by birthplace and acculturation. Cancer Epidemiol Biomarkers Prev. 2011;20(6):1064–77. https://doi.org/10.1158/1055-9965.EPI-11-0038.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Li Y, Wang Z, Yi D, Ma S. Racial differences in three mayor NHL subtypes: descriptive epidemiology. Cancer Epidemiol. 2015;39(1):8–13. https://doi.org/10.1016/j.canep.2014.12.001.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hoshiba T, Asamoto A, Yabuki Y. Decreasing seropositivity of cytomegalovirus of pregnant women in Japan. Nihon Rinsho. 1998;56(1):193–6 (PMID: 9465689).

    CAS  PubMed  Google Scholar 

  55. Chihara D, Ito H, Matsuda T, Shibata A, Katsumi A, Nakamura S, et al. Differences in incidence and trends of haematological malignancies in Japan and the United States. Br J Haematol. 2014;164(4):536–45. https://doi.org/10.1111/bjh.12659.

    Article  PubMed  Google Scholar 

  56. Howlader N, Noone AM, Krapcho M, et al. (Eds.). SEER Cancer Statistics Review, 1975–2014. National Cancer Institute, Bethesda, MD (https://seer.cancer.gov/csr/1975_2014/. Non-Hodgkin Lymphoma (Tab. 19.5), Hodgkin Lymphoma (Tab. 9.5), Leukemia (Tab. 13.5), Myeloma (Tab. 18.5), Age-Adjusted SEER Incidence Rates (Tab. 1.26, per 100,000 and age-adjusted to the 2000 US Std. Population).

  57. Yaqo RT, Jalal SD, Ghafour KJ, Hassan HA, Hughson MD. Non-Hodgkin lymphoma in the Middle East is characterized by low incidence rates with advanced age. J Glob Oncol. 2019;5:1–10. https://doi.org/10.1200/JGO.18.00241.

    Article  PubMed  Google Scholar 

  58. Bassig BA, Au X-Y, Mang Q, Ngan R, Morton LM, Dennis KM, et al. Subtype-specific incidence rates of lymphoid malignancies in Hong Kong compared to the United States, 2001–2010. Cancer Epidemiol. 2016;42:15–23. https://doi.org/10.1016/j.canep2016.02.007.

    Article  PubMed  Google Scholar 

  59. Monga N, Nastoupil L, Garside J, Quigley J, Hudson M, O’Donovan P, et al. Burden of illness of follicular lymphoma and marginal zone lymphoma. Ann Hematol. 2019;98(1):175–83. https://doi.org/10.1007/s00277-018-3501-8.

    Article  PubMed  Google Scholar 

  60. Zhou L, Deng Y, Li N, Zheng Y, Tian T, Zhai Z, et al. Global, regional, and national burden of Hodgkin lymphoma from 1990 to 2017: estimates from the 2017 Global Burden of Disease study. J Hematol Oncol. 2019;12:107. https://doi.org/10.1186/s13045-019-0799-1.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Global Burden of Disease Cancer Collaboration, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017;3(4):524–48. https://doi.org/10.1001/jamaoncol.2016.5688.

    Article  PubMed  Google Scholar 

  62. Liu W, Liu J, Song Y, Wang X, Zhou M, Wang L, et al. Union for China Lymphoma Investigators of the Chinese Society of Clinical Oncology Mortality of lymphoma and myeloma in China, 2004–2017: an observational study. J Hematol Oncol. 2019;12:22. https://doi.org/10.1186/s13045-019-0706-9.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Liu J, Liu W, Mi L, Zeng X, Cai C, Ma J, et al. Union for China Leukemia Investigators of the Chinese Society of Clinical Oncology Incidence and mortality of multiple myeloma in China, 2006–2016: an analysis of the Global Burden of Disease Study 2016. J Hematol Oncol. 2019;12:136. https://doi.org/10.1186/s13045-019-0807-5.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Turesson I, Bjorkholm M, Hveding Blimark C, Kristinsson S, Velez R, Landgren O. Rapidly changing myeloma epidemiology in the general population: increased incidence, older patients, and longer survival. Eur J Haematol. 2018;101(2):237–44. https://doi.org/10.1111/ejh.13083.

    Article  Google Scholar 

  65. Kazandjian D. Multiple myeloma epidemiology and survival, a unique malignancy. Semin Oncol. 2016;43(6):676–81. https://doi.org/10.1053/j.seminoncol.2016.11.004.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Winter JR, Taylor GS, Thomas OG, Jackson C, Lewis JEA, Stagg HR. Factors associated with cytomegalovirus serostatus in young people in England: a cross-sectional study. BMC Infect Dis. 2020;20(1):875. https://doi.org/10.1186/s12879-020-05572-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lin J, Lin W, Mi L, Zeng X, Cai C, Ma J, et al. Incidence and mortality of multiple myeloma in China, 2006–2016: an analysis of the Global Burden of Disease Study 2016. J Haematol Oncol. 2019;12:136. https://doi.org/10.1186/s13045-019-0807-5.

    Article  Google Scholar 

  68. Dong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y, et al. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020;9:14. https://doi.org/10.1186/s40164-020-00170-6.

    Article  PubMed  PubMed Central  Google Scholar 

  69. American Cancer Society, Inc.: Global Cancer Facts and Figures (4th ed., Source: GLOBOCAN 2018), Atlanta, GA, the US, American Cancer Society, Tables 4, 7, pp. 28, 59 (2018).

  70. Cowan AJ, Allen C, Barac A, Basaleem H, Bensenor I, Curado MP, et al. Global burden of multiple myeloma: a systematic analysis for the global burden of disease study 2016. JAMA Oncol. 2018;4(9):1221–7. https://doi.org/10.1001/jamaoncol.20182128.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Lee SJ, Tien HF, Park HJ, Kim JA, Lee DS. Gradual increase of chronic lymphocytic leukemia incidence in Korea, 1999–2010: comparison to plasma cell myeloma. Leuk Lymphoma. 2016;57(3):585–9. https://doi.org/10.3109/10428194.2015.1068307.

    Article  PubMed  Google Scholar 

  72. Wu SJ, Huang SY, Lin CT, Lin YJ, Chang CJ, Tien HF. The incidence of chronic lymphocytic leukemia in Taiwan, 1986–2005: a distinct increasing trend with birth-control effect. Blood. 2010;116(22):4430–5. https://doi.org/10.1182/blood-2010-05-285221.

    Article  CAS  PubMed  Google Scholar 

  73. Herbein G. The human cytomegalovirus, from oncomodulation to oncogenesis. Viruses. 2018;10(8):408. https://doi.org/10.3390/v10080408.

    Article  CAS  PubMed Central  Google Scholar 

  74. Kumar A, Coquard L, Pasquereau S, Russo L, Valmary-Degano S, Borg C, et al. Tumor control by human cytomegalovirus in a murine model of hepatocellular carcinoma. Mol Ther Oncolytics. 2016;3:16012. https://doi.org/10.1038/mto.2016.12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jurak I, Brune W. Induction of apoptosis limits cytomegalovirus cross-species infection. EMBO J. 2006;25:2634–42. https://doi.org/10.1038/sj.emboj.7601133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Erkes DA, Wilski NA, Snyder CM. Intratumoral infection by CMV may change the tumor environment by directly interacting with tumor-associated macrophages to promote cancer immunity. Hum Vaccin Immunother. 2017;13:1778–85. https://doi.org/10.1080/21645515.2017.1331795.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ben-Bassat I, Raanani P, Gale RP. Graft-versus-leukemia in chronic lymphocytic leukemia. Bone Marrow Transplant. 2007;39:441–6. https://doi.org/10.1038/sj.bmt.1705619.

    Article  CAS  PubMed  Google Scholar 

  78. Gustafsson B, Jernberg AG, Priftakis P, Bogdanovic G. No CMV DNA in Guthrie cards from children who later developed ALL. Pediatr Hematol Oncol. 2006;23(3):199–205. https://doi.org/10.1080/08880010500506677.

    Article  CAS  PubMed  Google Scholar 

  79. MacKenzie J, Gallagher A, Clayton RA, Perry J, Eden OB, Ford AM, et al. Screening for herpesvirus genomes in common acute lymphoblastic leukemia. Leukemia. 2001;15(3):415–42. https://doi.org/10.1038/sj.leu.2402049.

    Article  CAS  PubMed  Google Scholar 

  80. Bogdanovic G, Jernberg AG, Priftakis P, Grillner L, Gustafsson B. Human herpes virus 6 or Epstein-Barr virus were not detected in Guthrie cards from children who later developed leukaemia. Br J Cancer. 2004;91(5):913–5. https://doi.org/10.1038/sj.bjc.6602099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tomoka T, Montgomery ND, Eric Powers E, Dhungel MB, Morgan EA, Mulenga M, et al. Lymphoma and pathology in Sub-saharan Africa: current approaches and future directions. Clin Lab Med. 2018;38(1):91–100. https://doi.org/10.1016/j.cll.2017.10.007.

    Article  PubMed  Google Scholar 

  82. Fassas AB-T, Bolaños-Meade J, Buddharaju LN, Rapoport A, Cottler-Fox M, Chen T, et al. Cytomegalovirus infection and non-neutropenic fever after autologous stem cell transplantation: high rates of reactivation in patients with multiple myeloma and lymphoma. Br J Haematol. 2001;112:237–41. https://doi.org/10.1046/j.1365-2141.2001.02487.x.

    Article  CAS  PubMed  Google Scholar 

  83. Nguyen Q, Estey E, Raad I, Rolston K, Kantarjian H, Jacobson K, et al. Cytomegalovirus pneumonia in adults with leukemia: an emerging problem. Clin Infect Dis. 2001;32(4):539–45. https://doi.org/10.1086/318721.

    Article  CAS  PubMed  Google Scholar 

  84. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, et al. High-resolution donor-recipient HLAmatching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110(13):4576–83. https://doi.org/10.1182/blood-2007-06-097386.

    Article  CAS  PubMed  Google Scholar 

  85. Behrendt CE, Rosenthal J, Bolotin E, Nakamura R, Zaia J, Forman SJ. Donor and recipient cmv serostatus and outcome of pediatric allogeneic HSCT for acute leukemia in the era of CMVpreemptive therapy. Biol Blood Marrow Transplant. 2009;15(1):54–60. https://doi.org/10.1016/j.bbmt.2008.10.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Dieamant DC, Bonon SHA, Peres RMB, Costa CRC, Albuquerque DM, Miranda ECM, et al. Cytomegalovirus (CMV) genotype in allogeneic hematopoietic stem cell transplantation. BMC Infect Dis. 2013;13:310. https://doi.org/10.1186/1471-2334-13-310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ferrés M, Nervi B, Ramírez P. Prophylaxis against cytomegalovirus infection in pediatric and adult patients undergoing solid organ and hematopoietic stem cells transplantation. Rev Chilena Infectol. 2012;29(Suppl. 1):23–8. https://doi.org/10.4067/S0716-10182012000500004.

    Article  Google Scholar 

  88. Duval M, Klein JP, He W, Cahn J-Y, Cairo M, Camitta BM, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010;28(23):3730–8. https://doi.org/10.1200/JCO.2010.28.8852.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Teira P, Battiwalla M, Ramanathan M, Barrett MA, Ahn WA, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427–38. https://doi.org/10.1182/blood-2015-11-679639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cornelissen JJ, Carston M, Kollman C, King R, Dekker AW, Löwenberg B, et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood. 2001;97(6):1572–7. https://doi.org/10.1182/blood.v97.6.1572.

    Article  CAS  PubMed  Google Scholar 

  91. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. New Engl J Med. 2017;377(25):2433–44. https://doi.org/10.1056/NEJMoa1706640.

    Article  CAS  PubMed  Google Scholar 

  92. Fleming T, Dunne J, Crowley B. Ex vivo monitoring of human cytomegalovirus-specific CD8(+) T-Cell responses using the QuantiFERON-CMV assay in allogeneic hematopoietic stem cell transplant recipients attending an Irish hospital. J Med Virol. 2010;82(3):433–40. https://doi.org/10.1002/jmv.21727.

    Article  CAS  PubMed  Google Scholar 

  93. Ljungman P, Brand R, Hoek J, de la Camara R, Cordonnier C, Einsele H, et al. For the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis. 2014;59(4):473–81. https://doi.org/10.1093/cid/ciu364.

    Article  PubMed  Google Scholar 

  94. Ljungman P, de la Camara R, Milpied N, Volin L, Russell CA, Crisp A, et al. The Valacyclovir International Bone Marrow Transplant Study Group. Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants. Blood. 2002;99(8):3050–6. https://doi.org/10.1182/blood.v99.8.3050.

    Article  CAS  PubMed  Google Scholar 

  95. Mehta RS, Holtan SG, Wang T, Hemmer MT, Spellman SR, Arora M, et al. GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia. Blood Adv. 2019;3(9):1441–9. https://doi.org/10.1182/bloodadvances.2018030171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rubio MT, Savani BN, Labopin M, Polge E, Niederwieser D, Ganser A, et al. The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years—a report from the EBMT acute leukemia working party. J Hematol Oncol. 2016;9(1):65. https://doi.org/10.1186/s13045-016-0295-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dalle J-H, Balduzzi A, Bader P, Lankester A, Yaniv I, Wachowiak J, et al. Allogeneic stem cell transplantation from HLA-mismatched donors for pediatric patients with acute lymphoblastic leukemia treated according to the 2003 BFM and 2007 International BFM Studies: impact of disease risk on outcomes. Biol Blood Marrow Transplant. 2018;24(9):1848–55. https://doi.org/10.1016/j.bbmt.2018.05.009.

    Article  PubMed  Google Scholar 

  98. Roth-Guepin G, Canaani J, Ruggeri A, Labopin M, Finke J, Cornelissen JJ, et al. Allogeneic stem cell transplantation in acute lymphoblastic leukemia patients older than 60 years: a survey from the acute leukemia working party of EBMT. Oncotarget. 2017;8(68):112972–9. https://doi.org/10.18632/oncotarget.22934.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Debaugnies F, Busson L, Ferster A, Lewalle P, Azzi N, Aoun M, et al. Detection of Herpesviridae in whole blood by multiplex PCR DNAbased-microarray analysis after hematopoietic stem cell transplantation. J Clin Microb. 2014;52(7):2552–6. https://doi.org/10.1128/JCM.00061-14.

    Article  CAS  Google Scholar 

  100. Kielsen K, Enevold C, Heilmann C, Sengeløv H, Pedersen AE, Ryder LP, et al. Donor genotype in the interleukin-7 receptor α-chain predicts risk of graft-versus-host disease and cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2018;9:109. https://doi.org/10.3389/fimmu.2018.00109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Meijer E, Dekker AW, Rozenberg-Arska M, Weersink AJL, Verdonck LF. Influence of cytomegalovirus seropositivity on outcome after T cell-depleted bone marrow transplantation: contrasting results between recipients of grafts from related and unrelated donors. Clin Infecti Dis. 2002;35:703–12. https://doi.org/10.1086/342332.

    Article  Google Scholar 

  102. Broers AEC, van der Holt R, van Esser JWJ, Gratama J-W, Henzen-Logmans S, Kuenen-Boumeester V, et al. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMVdisease after allogeneic T-cell–depleted stem cell transplantation. Blood. 2000;95(7):2240–5. https://doi.org/10.1182/blood.V95.7.2240.

    Article  CAS  PubMed  Google Scholar 

  103. Jaskula E, Dlubek D, Tarnowska A, Lange J, Mordak-Domagala M, Suchnicki K, et al. Anti-CMV-IgG positivity of donors is beneficial for alloHSCT recipients with respect to the better short-term immunological recovery and high level of CD4+CD25high lymphocytes. Viruses. 2015;7(3):1391–408. https://doi.org/10.3390/v7031391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Michálek J, Horvath R. High incidence of Epstein-Barr virus, cytomegalovirus and human herpesvirus 6 infections in children with cancer. BMC Pediatr. 2002;2:1. https://doi.org/10.1186/1471-2431-2-1.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Kröger N, Zabelina T, Krüger W, Renges H, Stute N, Schrum J, et al. Patient cytomegalovirus seropositivity with or without reactivation is the most important prognostic factor for survival and treatment-related mortality in stem cell transplantation from unrelated donors using pretransplant in vivo T-cell depletion with anti-thymocyte globulin. Br J Haematol. 2001;113(4):1060–71. https://doi.org/10.1046/j.1365-2141.2001.02849.x.

    Article  PubMed  Google Scholar 

  106. Vdovin AS, Filkin SY, Yefimova PR, Sheetikov SA, Kapranov NM, Davydova YO, et al. Recombinant MHC tetramers for isolation of virus-specific CD8 + cells from healthy donors: potential approach for cell therapy of posttransplant cytomegalovirus infection. Biochemistry (Mosc). 2016;81(11):1371–83. https://doi.org/10.1134/S0006297916110146.

    Article  CAS  Google Scholar 

  107. Peric Z, Wilson J, Durakovic N, Ostojic A, Desnica L, Rezo Vranjes V, et al. Early human cytomegalovirus reactivation is associated with lower incidence of relapse of myeloproliferative disorders after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transpl. 2018;53(11):1450–6. https://doi.org/10.1038/s41409-018-0172-y.

    Article  CAS  Google Scholar 

  108. Mariotti J, Maura F, Spina F, Roncari L, Dodero A, Farina L, et al. Impact of cytomegalovirus replication and cytomegalovirus serostatus on the outcome of patients with B cell lymphoma after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(6):885–90. https://doi.org/10.1016/j.bbmt.2014.02.015.

    Article  PubMed  Google Scholar 

  109. Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, et al. CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: a report. Blood. 2013;122(19):3359–64. https://doi.org/10.1182/blood-2013-05-499830.

    Article  CAS  PubMed  Google Scholar 

  110. Piñana JL, Martino P, Barba P, Margall N, Roig MC, Valcárcel D, et al. Cytomegalovirus infection and disease after reduced intensity conditioning allogeneic stem cell transplantation: single-centre experience. Bone Marrow Transplant. 2010;45:534–42. https://doi.org/10.1038/bmt.2009.180.

    Article  PubMed  Google Scholar 

  111. Al-Sweedan S, Al-Seraihy A, Al-Ahmari A, Al-Jefri A, Mohammed V, Jafri R, et al. Factors determining the outcome of hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia at King Faisal Specialist Hospital and Research Center, Riyadh. Saudi Arabia J Pediatr Hematol/Oncol. 2017;39(1):33–7. https://doi.org/10.1097/MPH.0000000000000679.

    Article  CAS  Google Scholar 

  112. Al-Hajjar S, Al Seraihi A, Al Muhsen S, Ayas M, Al Jumaah S, Al Jefri A, et al. Cytomegalovirus infections in unrelated cord blood transplantation in pediatric patients: incidence, risk factors, and outcomes. Hematol Oncol Stem Cell Ther. 2011;4(2):67–72. https://doi.org/10.5144/1658-3876.2011.67.

    Article  PubMed  Google Scholar 

  113. Hussein AA, Al-Antary ET, Najjar R, Al-Hamdan DS, Al-Zaben A, Frangoul H. Incidence and risk factors for cytomegalovirus (CMV) reactivation following autologous hematopoietic stem cell transplantation in children. Pediatr Blood Cancer. 2015;62(6):1099–101. https://doi.org/10.1002/pbc.25292.

    Article  PubMed  Google Scholar 

  114. Al Mana H, Yassine HM, Younes NN, Al-Mohannadi A, Al-Sadeq DW, Alhababi D, et al. The current status of cytomegalovirus (CMV) prevalence in the MENA region: a systematic review. Pathogens. 2019;8(4):213. https://doi.org/10.3390/pathogens8040213.

    Article  CAS  PubMed Central  Google Scholar 

  115. Cohen L, Yeshurun M, Shpilberg O, Ram R. Risk factors and prognostic scale for cytomegalovirus (CMV) infection in CMV-seropositive patients after allogeneic hematopoietic cell transplantation. Transpl Infect Dis. 2015;17(4):510–7. https://doi.org/10.1111/tid.12398.

    Article  CAS  PubMed  Google Scholar 

  116. Valadkhani B, Kargar M, Ashouri A, Hadjibabaie M, Gholami K, Ghavamzadeh A. The risk factors for cytomegalovirus reactivation following stem cell transplantation. J Res Pharm Pract. 2016;5(1):63–9. https://doi.org/10.4103/2279-042X.176554.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Safabakhsh H, Tehranian F, Tehranian B, Hatami H, Karimi G, Shahabi M. Prevalence of anti-CMV antibodies in blood donors in Mashhad. Iran Iran J Epidemiol. 2013;9(1):52–7.

    Google Scholar 

  118. Sepehrvand N, Khameneh ZR, Eslamloo HRF. Survey the seroprevalence of CMV among hemodialysis patients in Urmia, Iran. Saudi J Kidney Dis Transpl. 2010;21(2):363–7 (PMID: 20228534).

    PubMed  Google Scholar 

  119. Behzad-Behbahani A, Ehsanipour F, Alborzi A, Nourani H, Ramzi M, Rasoli M. Qualitative detection of human cytomegalovirus DNA in the plasma of bone marrow transplant recipients: Value as a predictor of disease progression. Exp Clin Transplant. 2004;2(1):196–200 (PMID: 15859928).

    CAS  PubMed  Google Scholar 

  120. Ziyaeyan M, Sabahi F, Alborzi A, Mahboudi F, Kazemnejad A, Ramzi M, et al. Diagnosis and monitoring of human cytomegalovirus infection in bone marrow transplant recipients by quantitative competitive PCR. Exp Clin Transplant. 2006;4(1):470–4 (PMID: 16827646).

    PubMed  Google Scholar 

  121. Handous I, Achour B, Marzouk M, Rouis S, Hazgui O, Brini I, et al. Co-infections of human herpesviruses (CMV, HHV-6, HHV-7 and EBV) in nontransplant acute leukemia patients undergoing chemotherapy. Virol J. 2020;17:37. https://doi.org/10.1186/s12985-020-01302-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gawad AA, Hashish M, Abaza A, El-Kayal A. Cytomegalovirus immunoglobulin G avidity index among blood donors in Alexandria. Egypt Cent Eur J Public Health. 2016;24(4):314–20. https://doi.org/10.21101/cejph.a4157.

    Article  PubMed  Google Scholar 

  123. Zekri ARN, Mohamed WS, Samra MA, Sherif GM, El-Shehaby AM, El-Sayed MH. Risk factors for cytomegalovirus, hepatitis B and C virus reactivation after bone marrow transplantation. Transpl Immunol. 2004;13(4):305–11. https://doi.org/10.1016/j.trim.2004.10.001.

    Article  PubMed  Google Scholar 

  124. Loutfy SA, Abo-Shadi MA, Fawzy M, El-Wakil M, Metwally SA, Moneer MM, et al. Epstein-Barr virus and cytomegalovirus infections and their clinical relevance in Egyptian leukemic pediatric patients. Virol J. 2017;14(1):46. https://doi.org/10.1186/s12985-017-0715-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. George B, Pati N, Gilroy N, Ratnamohan M, Huang G, Kerridge I, et al. Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transpl Infect Dis. 2010;12(4):322–9. https://doi.org/10.1111/j.1399-3062.2010.00504.x.

    Article  CAS  PubMed  Google Scholar 

  126. Devasia AJ, Mammen S, Korula A, Abraham A, Fouzia NA, Lakshmi KM, et al. A low incidence of cytomegalo virus infection following allogeneic hematopoietic stem cell transplantation despite a high seroprevalence. Indian J Hematol Blood Transfus. 2018;34(4):636–42. https://doi.org/10.1007/s12288-018-0960-y.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Azanan MS, Abdullah NK, Chua LL, Lum SH, Ghafar SSA, Kamarulzaman A, et al. Immunity in young adult survivors of childhood leukemia is similar to the elderly rather than age-matched controls: role of cytomegalovirus. Eur J Immunol. 2016;6(7):1715–26. https://doi.org/10.1002/eji.201646356.

    Article  CAS  Google Scholar 

  128. Du J, Liu J, Gu J, Zhu P. HLA-DRB1*09 is associated with increased incidence of cytomegalovirus infection and disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13(12):1417–21. https://doi.org/10.1016/j.bbmt.2007.09.003.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank all participants in this study and appreciate an excellent assistance of the attending clinical staff and services. We thank all the healthcare workers around the globe who are working hard to help humanity in the fight against the B-cell cancers. The authors owe particular gratitude and deeply appreciate the two anonymous Journal referees for their very careful review of this manuscript and insightful and constructive recommendations. They contributed valuable suggestions, enriched the substance of arguments, and improved clarity of the previous draft. We stress that our exploration is far from exhaustive. Indeed, much still remains to be learned about the antioncogenicity of CMV in various oncological settings.

Funding

We would like to acknowledge the research funding within the scope of a project under financing grants by MPNTR of the National Ministry of Education, Science and Technological Development, Projects Nos. 1750-73 and 41004. The National Ministry as funding source had no role in study design, data collection and interpretation, or the decision to submit this work for publication.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to the study conception and design. The first draft was written by MJ. MJ and AK conducted laboratory investigation, performed the experiments, collected laboratory information and, interpreted and analyzed the data. Coordination and supervision of data and sample collection was performed by MT, BM, IĐ and VS. IS analyzed and interpreted the data. TJ designed the methodology, managed resource acquisition, project administration and overall supervision, and was responsible for the research activity planning and execution. MB, JP, NM and SFV collected patient record data and performed laboratory experiments. All authors read, critically revised, and approved the final manuscript.

Corresponding author

Correspondence to Marko Janković.

Ethics declarations

Ethics approval and consent to participate

This work was performed in accordance with principles of 1964 Helsinki Declaration and its later amendments. Approval was granted by the University Clinical Centre of Serbia, University of Belgrade Ethical Review Board and Faculty of Medicine. Guidelines of Good Clinical Practice were observed. Document of informed approval was obtained from all consenting participants included in the study. The security and privacy of patient's health was not violated in this study.

Consent for publication

Not applicable.

Competing interests

The authors declare that research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Janković, M., Knežević, A., Todorović, M. et al. Cytomegalovirus infection may be oncoprotective against neoplasms of B-lymphocyte lineage: single-institution experience and survey of global evidence. Virol J 19, 155 (2022). https://doi.org/10.1186/s12985-022-01884-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12985-022-01884-1

Keywords

  • Cytomegalovirus
  • B-cell malignancies
  • Global
  • Seroprevalence
  • Oncoprotection