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Blood Podcast
Epstein-Barr virus genomic variants in human disease states, somatic GATA1 mutations and leukemia in Down syndrome, and new definitions for high-risk multiple myeloma
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Welcome to the September 25, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood, A Journal of the American Society of Hematology. Today we'll learn more about relationships between Epstein Barr virus, genomic variants and human diseases, including hematological malignancies, the presence and timing of somatic GATA1 mutations and their relationship to a Down syndrome, specific form of leukemia, and new definitions for high risk multiple myeloma that emphasize the presence of two or more high risk cytogenetic abnormalities. We first examined data in the Blood article entitled association of Epstein Barr Viral Genomic Alterations to Human Pathologies by Hetet Thiri Kain of the Nagoya City University Graduate School of Medical Sciences in Nagoya, Japan, and colleagues. Over 90% of the human population is infected with Epstein Barr virus, or ebv. EBV primarily infects B lymphocytes, where it establishes a lifelong latent, usually asymptomatic, infection. In some people, EBV infection leads to the development of hematological malignancies such as Burkitt lymphoma, Hodgkin lymphoma, and T cell lymphomas. EBV can also infect epithelial cells and is associated with the development of nasopharyngeal carcinoma and a subset of gastric carcinomas. Other disease states associated with EBV infection include infectious mononucleosis, systemic lupus erythematosus, and multiple sclerosis. The EBV genome contains about 90 genes, many of whose protein products are involved in regulating viral latency, replication, and immune evasion. Many of these gene products have also been implicated in the development of cancer and or autoimmune conditions. Less is known, however, about how single nucleotide or structural variants in EBV genes impact their roles in these pathologies. The authors of the first paper that we're discussing investigated EBV genomic variants in 990 EBV genomes, 319 of which they sequenced themselves and 671 of which were derived from publicly available databases. The EBV genomic sequences came from patients with a range of EBV related conditions as well as healthy individuals. Representing a wide geographic distribution. The authors identified over 22,000 single nucleotide variants, or SNVs, in the 990 EBV genomes. These SNVs formed six clusters, primarily driven by the geographical distribution of the samples. Four clusters were associated with EBV genomes from Asia. Genomes from Africa, Europe, and the Americas formed another cluster. The remaining cluster was mainly composed of genomes from EBV type 2, one of the two main types of EBV. The authors identified several SNV hotspots that appeared to have been acquired independently through convergent evolution. One hotspot was found in the central homology domain of the EBNA3B protein, which is a transcription factor involved in regulation of viral latency. This hotspot was found in multiple EBV related disease states. Additional SNV hotspots were found in the transactivation domain of Ebna2, another transcription factor that regulates host cell gene transcription, and LMP1, a gene whose expression has been detected in many EBV associated cancers. This gene also appears to be involved in B cell transformation. In addition to SNVs, the authors explored EBV genomic structural variants. They identified 163 intragenic deletions and 18 inversions. In four cases, EBV was integrated into the human genome, a property associated with tumorigenesis. Large deletions were common in patients with active chronic EBV infections and hematological malignancies, occurring in 20 to 46% of cases. They were less common in patients with epithelial malignancies and in healthy individuals, occurring in only 5% of cases in hematological malignancies. These deletions often targeted viral microrna clusters, potentially upregulating viral reactivation and thus influencing lymphoma development. The EBNA3B gene in particular, was the site of multiple large deletions found primarily in patients with hematologic malignancies. This finding suggested that the Ebna3B protein, a transcription factor, might act as a tumor suppressor. To test this hypothesis, the authors created lymphoblastoid cell lines in which EBNA3B expression was knocked out. Gene expression analysis showed that EBNA3B knockout was associated with downregulation of PTEN and RB1, both well known tumor suppressors. This suggests a role for EBNA3B in tumor development. Overall, the authors observed changes in EBV genomes in patients with lymphoma that would tend to preserve immune evasion, with deletions occurring in genes responsible for regulating viral latency and tumor suppression. These genomic alterations might represent new therapeutic targets in EBV associated hematological malignancies. In an accompanying commentary, Paul Farrell of Imperial College London in the UK said that this work provides a more comprehensive picture of EBV genomic variation than previously available. This knowledge is likely to have implications for diagnostics, risk assessment and immunization against EBV related conditions. Next up we'll discuss findings from the Blood article entitled Clinical significance of pre leukemic somatic GATA1 mutations in children with down syndrome by Natalina Elliot of the University of Oxford in Oxford, UK and colleagues. Children with down syndrome or trisomy 21 have a high risk of developing a Down syndrome specific myeloid leukemia known as mlds. This leukemia is preceded by a neonatal leukemic syndrome known as known as transient abnormal myelopoiesis or tam. Not all newborns with TAM go on to develop mlds. In addition, the risk of developing mlds is transient, occurring within a relatively narrow timeframe between birth and four years. Nearly all cases of TAM and MLDS carry somatic mutations in the GATA1 gene, which encodes the GATA1 transcription factor. The mutations associated with MLDS result in the production of a shortened form of the transcription factor known as GATA1S. This association between GATA1S mutations and leukemia occurs only within the context of trisomy 21. Although the link between GATA1S and MLDS is well established, the natural history and underlying pathophysiology of this leukemia are not well known. The authors of the second paper that we're discussing today prospectively studied 450 newborns with down syndrome to better understand the timing and prevalence of GATA1S mutations and their relationship to the development of TAM and MLDS. The authors followed these newborns from birth to four years using next generation sequencing to periodically test for GATA1S mutations in peripheral blood and and performing detailed hematologic and clinical evaluations. 113 or about 1/4 of the 450 newborns with down syndrome had GATA1S mutations at birth. The presence of a GATA1S mutation did not correlate with birth weight, the presence of congenital heart conditions or gastrointestinal anomalies associated with trisomy 21 or pregnancy related factors. GATA1S mutations were typically detected from 28 weeks gestation on occurring most frequently at 34 to 35 weeks gestation. Testing of 57 available early fetal samples found that GATA1S mutations were rare before 20 weeks gestation, occurring in fewer than 4% of cases. None of the newborns who lacked GATA1S mutations at birth developed them later. These findings suggest that GATA1S mutations develop mostly during the third trimester of fetal development and that conditions favorable for GATA1S clonal selection and survival are no longer present after birth. None of the newborns who lacked GATA1S mutations went on to develop MLDS, supporting the idea that this mutation is necessary for MLDS to occur. 54 or 48% of the 113 newborns with GATA1S mutations had clinical TAM. Clinical TAM is characterized by abnormal BLAST counts of greater than 10% and clinical features such as hepatomegaly, splenomegaly, effusions, and skin rash. The other 59 newborns with GATA1S mutations had silent TAM in which blasts were less than 10% and there were no clinical manifestations. The presence of clinical TAM was not related to the number or types of GATA1S mutations presentation. Instead, TAM correlated with a higher variant allele frequency OR VAF for GATA 1s. GATA 1 SVAF was also positively correlated with BLAST percentage, leukocyte levels, and measures of abnormal erythrocyte and platelet production. GATA1S mutations were transient in most cases. GATA1S VAFS fell rapidly with age, becoming undetectable by the age of 6 months. In in most cases, 7 newborns had GATA1S VAFs that did not decline with age. All of these cases later developed MLDs at a median age of 17.5 months. One of these cases had silent TAM. Neither blast percentage nor an increase in GATA1svaf were consistent early indicators of transformation to MLDs. Instead, the authors found that falling platelet counts were the earliest indicator of impending mlds development. This finding suggests that monitoring platelet counts could be a readily available screening method for leukemia in newborns with down syndrome and GATA1S mutations. In an accompanying commentary, Jeffrey McGee of the Washington University School of Medicine in St. Louis, Missouri, said that these findings on the natural history of GATA1S mutations and TAM will help to simplify risk assessment and monitoring of newborns with down syndrome for for the development of mlds. In the final part of today's podcast, we'll discuss findings in the Blood article entitled New Prognostic Systems for Multiple Myeloma in the Context of Contemporary Therapies by Andrew Spencer of the Alfred Health Monash University in Melbourne, Australia. Newer treatments, including three and four drug combination regimens, have greatly improved outcomes for patients with both transplant eligible and transplant ineligible multiple myeloma in recent years. Despite these successes, about 20% of patients receiving these treatments experience early relapse and poor outcomes. New treatment approaches are needed for these high risk patients the International Staging System for newly Diagnosed multiple myeloma has been instrumental in stratifying patients for clinical trial development of new therapies. However, the lack of clinical benefit in a substantial proportion of patients suggests that newer models may be needed to identify the highest risk patients, particularly in the context of contemporary therapeutic approaches. The third paper that we're discussing today is a commentary on two recent publications in the Journal of Clinical Oncology that revisited the definition of high risk multiple myeloma. Both both publications included more recent clinical trial datasets, including some unpublished data. These two publications used different methodologies but came to similar conclusions. Both include the recommendation that high risk multiple myeloma should be defined primarily by the presence of two or more high risk cytogenetic abnormalities rather than a single high risk cytogenetic abnormality as used in previous definitions. One publication by Herve Avette Loiseau of the University Cancer center of Toulouse in Toulouse, France, and colleagues describes the consensus recommendations of an expert panel convened by the International Myeloma Society and International Myeloma Working Group. The expert panel used newer clinical data, new evidence on molecular and cytogenetic risk, and more contemporary risk stratification methods to recommend a new definition for high risk disease. They used the revised International Staging System Model, or ris, as a starting point. The RIS model combines widely available serum biomarkers with high risk cytogenetic abnormalities that are identifiable using fluorescence in situ hybridization. Although genomic data continues to accumulate and can be used to identify high risk disease, these markers are more readily available. The panel's new definition of high risk multiple myeloma includes multiple high risk scenarios, several of which specify the presence of more than one high risk cytogenetic abnormality. A significant change from the previous definition is that translocations T414, T1416 and T1420 are no longer considered high risk on their own, but instead must CO occur with 1q gain or amplification and or 1p32 deletion. This change helps to resolve the heterogeneity found in patients with T414 in particular, many of whom do not have high risk characteristics. Another change is the inclusion of one P32 deletion as a high risk marker when it is biallelic or when it occurs together with 1Q gain or amplification. This change considers recent data showing poor outcomes for patients with these cytogenetic changes, the only singly occurring cytogenetic alteration that would be considered high risk in this new definition would be deletion of chromosomal region 17p, but only if it is present at 20% clonal fraction or above or in combination with a TP53 mutation. The new definition retains beta 2 microglobulin as a marker of high risk disease in the absence of high risk cytogenetic abnormalities when present at or above 5.5 milligrams per liter in the context of preserved renal function. The second publication by Martin F. Kaiser of the Royal Marsden Hospital NHS Foundation Trust in London, UK and colleagues reported results of a multi trial clinical data analysis that focused specifically on the impact of multiple high risk cytogenetic abnormalities on patient outcomes. The authors of this study analyzed 24 clinical trials that included patients with both newly diagnosed and relapsed refractory multiple myeloma. Trials were included if data on high risk cytogenetic abnormalities including T414, T1416, 17P deletion and 1Q gain were available for the majority of patients. In order to overcome obstacles related to data sharing, each clinical trial group was asked to perform an independent analysis of outcomes outcomes for patients with single or multiple high risk cytogenetic abnormalities using a standardized algorithm. This analysis, which included data from nearly 14,000 patients, found that the presence of two or more high risk cytogenetic abnormalities was associated with a significantly higher risk of poor outcomes compared with only one high risk cytogenetic abnormality. For example, the hazard ratio for Overall survival was 2.94 in in patients with two or more high risk cytogenetic abnormalities compared with 1.69 for patients with only one such abnormality. Andrew Spencer, author of the commentary published in Blood, concluded that, taken together, these two publications provide a potential new framework for designing trials to identify novel treatment approaches for patients with high risk multiple myeloma. In addition to emphasizing the importance of two or more high risk abnormalities, these two publications reinforce the idea that there is a high risk population of patients with multiple myeloma who are deriving little or no benefit from contemporary therapies. For a list of additional authors as well as more detailed articles and commentaries on which this podcast is based, please go to bloodjournal.org be sure to join us next week for another episode of Blood Podcast. Thank you for listening.