Search

Keywords: Myelodysplastic syndromes; del(5q); non-del(5q); mutations; lenalidomide EN Myelodysplastic syndromes del(5q) non-del(5q) mutations lenalidomide e133 e137 5 05/19/20 20200515 NES 200515 Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterised by ineffective haematopoiesis leading to peripheral blood cytopenias and an increased risk of transformation to acute myeloid leukaemia (AML) (Haferlach I et al. i , [5]; Makishima I et al. i , [8]). Lenalidomide (LEN) has been approved for the treatment of patients with del(5q) low-risk MDS and transfusion dependence. We collected 74 samples from patients with MDS at diagnosis or treatment-naïve with LEN follow-up treatment of two or more cycles; 32 patients presented with del(5q), while 42 patients did not have del(5q) in their karyotype (Table S1). As expected, responders were mainly classified in MDS with isolated del(5q) (71%), while non-responders were enriched in MDS with ring sideroblasts and with single lineage dysplasia (MDS-RS-SLD; 33%), and MDS with multilineage dysplasia (MDS-MLD; 26%; Table 1). 1 TableClinical characteristics of the patients. [Extracted from the article]

The article presents a case study of a 9 month-old infant with familial thrombocytopenia with a SAMD9L variant, marrow normocellularity, and the absence of megakaryocytes. Topics discussed include to assess the effects of rare variants identified in adults with myelodysplastic syndromes (MDSs) and bone marrow failure (BMFs); tested the growth of HEK293 cells with inducible expression of SAMD9 or SAMD9L proteins; and mentions analyzation of copy number alterations (CNAs).

Summary: Despite the absence of mutations in the DNA repair machinery in myeloid malignancies, the advent of high‐throughput sequencing and discovery of splicing and epigenetics defects in chronic myelomonocytic leukaemia (CMML) prompted us to revisit a pathogenic role for genes involved in DNA damage response. We screened for misregulated DNA repair genes by enhanced RNA‐sequencing on bone marrow from a discovery cohort of 27 CMML patients and 9 controls. We validated 4 differentially expressed candidates in CMML CD34+ bone marrow selected cells and in an independent cohort of 74 CMML patients, mutationally contextualized by targeted sequencing, and assessed their transcriptional behavior in 70 myelodysplastic syndrome, 66 acute myeloid leukaemia and 25 chronic myeloid leukaemia cases. We found BAP1 and PARP1 down‐regulation to be specific to CMML compared with other related disorders. Chromatin‐regulator mutated cases showed decreased BAP1 dosage. We validated a significant over‐expression of the double strand break‐fidelity genes CDKN1A and ERCC1, independent of promoter methylation and associated with chemorefractoriness. In addition, patients bearing mutations in the splicing component SRSF2 displayed numerous aberrant splicing events in DNA repair genes, with a quantitative predominance in the single strand break pathway. Our results highlight potential targets in this disease, which currently has few therapeutic options. [ABSTRACT FROM AUTHOR]

Isolate loss of chromosome Y (-Y) in myelodysplastic syndromes (MDS) is associated to a better outcome but it is also well described as an age-related phenomenon. In this study we aimed to analyze the prognostic impact of −Y in the context of the IPSS-R cytogenetic classification, evaluate the clinical significance of the percentage of metaphases with isolated −Y, and test whether finding −Y may predispose to over-diagnose MDS in patients with borderline morphological features. We evaluated 3581 male patients from the Spanish MDS Registry with a diagnosis of MDS or chronic myelomonocytic leukemia (CMML). −Y was identified in 177 patients (4.9%). Compared with the 2246 male patients with normal karyotype, −Y group showed a reduced risk of leukemic transformation that did not translate into a survival advantage. The overall survival and the risk of leukemic transformation were not influenced by the percentage of metaphases with −Y. The −Y group was not enriched in patients with minor morphologic traits of dysplasia, suggesting that the better outcome in the −Y group cannot be explained by enrichment in cases misdiagnosed as MDS. In conclusion, our results support the current recommendation of classifying patients with −Y within the very good risk category of the IPSS-R for MDS and rule out a selection bias as a possible explanation of this better outcome. An analysis of the molecular basis of MDS with isolated −Y would be of interest as it may provide a biological basis of protection against progression to acute leukemia. [ABSTRACT FROM AUTHOR]

Although the majority of MDS patients fail to achieve clinical improvement to approved therapies, some patients benefit from treatment. Predicting patient response prior to therapy would improve treatment effectiveness, avoid treatment-related adverse events and reduce healthcare costs. Three separate cohorts of MDS patients were used to simulate drug response to lenalidomide alone, hypomethylating agent (HMA) alone, or HMA plus lenalidomide. Utilizing a computational biology program, genomic abnormalities in each patient were used to create an intracellular pathway map that was then used to screen for drug response. In the lenalidomide treated cohort, computer modeling correctly matched clinical responses in 37/46 patients (80%). In the second cohort, 15 HMA patients were modeled and correctly matched to responses in 12 (80%). In the third cohort, computer modeling correctly matched responses in 10/10 patients (100%). This computational biology network approach identified GGH overexpression as a potential resistance factor to HMA treatment and paradoxical activation of beta-catenin (through Csnk1a1 inhibition) as a resistance factor to lenalidomide treatment. We demonstrate that a computational technology is able to map the complexity of the MDS mutanome to simulate and predict drug response. This tool can improve understanding of MDS biology and mechanisms of drug sensitivity and resistance. [ABSTRACT FROM AUTHOR]

Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6 , GATA2 , SAMD9 , SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical care. We illustrate the importance of natural history studies and the need for respective registries for future evidence-based recommendations that shall be updated as new evidence-based standards are established. [ABSTRACT FROM AUTHOR]

Optical Genome Mapping (OGM) is rapidly becoming adopted as a first-line test for genome structural variation assessment in clinical genetics laboratories worldwide. OGM has been shown in multiple recent publications to have several benefits over the standard of care assessment (e.g. karyotype, FISH, and chromosomal microarray) in hematologic malignancies, including the ability to combine the observations of current standard of care techniques into a single assay, to improve on the routine detection of sub-microscopic variations (e.g. insertions, tandem duplications) that are not detected in their structural context by chromosomal microarray, and to detect and clarify complex karyotypes identifying critical cancer driver alterations and molecular therapeutic targets. Considering its potential to serve as a powerful diagnostic tool for hematologic malignancies, guidelines for the implementation of OGM in a clinical laboratory that include validation, filtering, and interpretative standards will be a great resource to the community, but formal standardized guidelines are currently lacking. To address this, we created an International OGM Working Group that includes 13 scientists from nine renowned institutions from five countries (Canada, USA, The Netherlands, Belgium and Spain) that are leading the implementation of OGM in their laboratories and are collaborating on a global standard for the assessment of hematologic malignancies. This presentation will review the validation and interpretative recommendations proposed by the working group to assist laboratories in the uniform implementation of OGM for clinical use in the evaluation of hematologic malignancies. [ABSTRACT FROM AUTHOR]

Abstract: In patients with myelodysplastic syndromes (MDS), chromosome anomalies are detected by conventional cytogenetic studies (CCS) and/or interphase fluorescence in situ hybridization (FISH) of bone marrow (BM) samples and provide prognostic and diagnostic information, which can direct therapy. Whether peripheral blood (PB) can be substituted for bone marrow in these cases and can provide the same information remains unknown. Concurrent BM and PB specimens collected from 100 patients with recently diagnosed MDS were studied using both CCS and FISH. While 68% of BM samples showed an abnormal karyotype by CCS, only 31% of PB samples were abnormal by CCS. In 12% of patients, FISH and CCS were discordant due to the inability of the FISH panel to detect all possible abnormalities. However, only one case (1%) had a cryptic abnormality detected by FISH. BM and PB FISH were discordant in 3% of cases, most likely due to the smaller clone size in PB vs. BM. While PB should not be substituted for BM at diagnosis, it is a viable alternative for monitoring patients using the appropriate FISH probe(s). [Copyright &y& Elsevier]

Abstract: Comparative genomic hybridization (CGH) allows the analysis of chromosomal imbalances without requiring cell cultures and is more reliable than conventional cytogenetic studies for detecting gains, losses, and amplified regions. To perform CGH on cervical lesions, some authors obtain the tumoral DNA from frozen or paraffin-embedded biopsies. Others use laser microdissected material from paraffin-embedded samples, followed by degenerate oligonucleotide primer-polymerase chain reaction (DOP-PCR). In all these cases, surgery is required to obtain the sample. In our study, we obtained DNA from a cotton-lint cervical sample obtained from the pathological zone using a colposcopy technique. Chromosomal alterations were found in 9 (81%) of the 11 cases analyzed. The most frequent alterations affected the 3p12, 4q25, 5q15∼q21, and 18p11 regions. Satisfactory results have been observed when the cotton-lint cervical sample has been used as the source for obtaining DNA. In the laboratory, the manipulation of this type of sample obtained by a noninvasive system is much simpler, easier, and faster than the obtained with a conventional biopsy. [Copyright &y& Elsevier]

Abstract: Mutations in the TP53 gene, particularly multihit alterations, have been associated with unfavorable clinical features and prognosis in patients diagnosed with myelodysplastic syndrome (MDS). Despite this, the role of TP53 gene aberrations in MDS with isolated deletion of chromosome 5 [MDS-del(5q)] remains unclear. This study aimed to assess the impact of TP53 gene mutations and their allelic state in patients with MDS-del(5q). To that end, a comprehensive analysis of TP53 abnormalities, examining both TP53 mutations and allelic imbalances, in 682 patients diagnosed with MDS-del(5q) was conducted. Twenty-four percent of TP53-mutated patients exhibited multihit alterations, whereas the remaining patients displayed monoallelic mutations. TP53-multihit alterations were predictive of an increased risk of leukemic transformation. The impact of monoallelic alterations was dependent on the variant allele frequency (VAF); patients with TP53-monoallelic mutations and VAF <20% exhibited behavior similar to TP53 wild type, and those with TP53-monoallelic mutations and VAF ≥20% presented outcomes equivalent to TP53-multihit patients. This study underscores the importance of considering TP53 allelic state and VAF in the risk stratification and treatment decision-making process for patients with MDS-del(5q)., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Germline predisposition to myeloid neoplasms can be suspected in patients younger than 50 years or when harboring mutations with a variant allele frequency (VAF) higher than 30% for point mutations in specific genes. To investigate the VAF thresholds' accuracy we have explored the prevalence of germline variants below the 30% VAF threshold., Methods: A total of 40 variants with VAF lower than 30% in bone marrow samples of myeloid neoplasm patients were selected and studied in CD3 + cells., Results: All the selected variants were not found in CD3 + cells except one variant in the SF3B1 gene. However, the whole series was found somatic. Selected variants were also evaluated with our previously studied series of 52 variants with VAF higher than 30%., Conclusion: Our study suggests that variants with VAF below 30% are strong somatic candidates but the variants with VAF higher than 30% cannot be considered of germline origin., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M)., Patients and Methods: We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies., Results: Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy ( P = .001)., Conclusion: These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

Purpose: Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M., Methods: A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed., Results: IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score., Conclusion: IPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score.

SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production., Significance: MDS-RS are characterized by significant anemia. Patients with MDS-RS die from a shortage of red blood cells and the side effects of iron overload due to their constant need for transfusions. Our study has implications for the development of therapies to achieve long-lasting hematologic responses. This article is highlighted in the In This Issue feature, p. 476., (©2022 The Authors; Published by the American Association for Cancer Research.)

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19- (pre)-leukemic cells represent an "early progenitor origin-related" mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19-CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19-CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19-CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19-CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19- relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged., (© 2022 by The American Society of Hematology.)

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms., (© 2021 by The American Society of Hematology.)

Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication., Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed., Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations ( SF3B1 , SRSF2 , and U2AF1 ) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1 - and SRSF2 -related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features., Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis., Competing Interests: Manja MeggendorferEmployment: MLL Munich Leukemia Laboratory Marianna RossiConsulting or Advisory Role: Pfizer, Celgene, IQvia, Janssen Emanuele AngelucciHonoraria: Celgene, Vertex Pharmaceuticals Incorporated (MA) and CRISPR Therapeutics AG (CH)Consulting or Advisory Role: Novartis, Bluebird BioTravel, Accommodations, Expenses: Janssen-Cilag Massimo BernardiHonoraria: CelgeneConsulting or Advisory Role: PfizerTravel, Accommodations, Expenses: Medac, Amgen, Sanofi, Jazz Pharmaceuticals, BioTest, Abbvie, Takeda Lorenza BorinLeadership: CelgeneSpeakers' Bureau: GenzymeTravel, Accommodations, Expenses: Genzyme Benedetto BrunoHonoraria: Jazz Pharmaceuticals, Novartis, AmgenResearch Funding: Amgen Valeria SantiniHonoraria: Celgene/Bristol-Myers Squibb, Novartis, Janssen-CilagConsulting or Advisory Role: Celgene/Bristol-Myers Squibb, Novartis, Menarini, Takeda, PfizerResearch Funding: CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Celgene Andrea BacigalupoHonoraria: Pfizer, Therakos, Novartis, Sanofi, Jazz Pharmaceuticals, Riemser, Merck Sharp & Dohme, Janssen-Cilag, Gilead Sciences, Kiadis Pharma, Astellas PharmaConsulting or Advisory Role: Novartis, Kiadis Pharma, Gilead Sciences, Astellas PharmaSpeakers' Bureau: Pfizer, Therakos, Novartis, Sanofi, Riemser, Merck Sharp & Dohme, Adienne, Jazz PharmaceuticalsTravel, Accommodations, Expenses: Sanofi, Therakos, Jazz Pharmaceuticals Maria Teresa VosoHonoraria: Celgene/Jazz, AbbvieConsulting or Advisory Role: Celgene/JazzSpeakers' Bureau: CelgeneResearch Funding: Celgene Esther OlivaHonoraria: Celgene, Novartis, Amgen, Alexion PharmaceuticalsConsulting or Advisory Role: Amgen, Celgene, NovartisSpeakers' Bureau: Celgene, NovartisPatents, Royalties, Other Intellectual Property: Royalties for QOL-E instrument Francesco PassamontiSpeakers' Bureau: Novartis, AOP Orphan Pharmaceuticals Niccolò BolliConsulting or Advisory Role: JanssenSpeakers' Bureau: Celgene, Amgen Alessandro RambaldiHonoraria: Amgen, OmerosConsulting or Advisory Role: Amgen, Omeros, Novartis, Astellas Pharma, Jazz PharmaceuticalsTravel, Accommodations, Expenses: Celgene Wolfgang KernEmployment: MLL Munich Leukemia LaboratoryLeadership: MLL Munich Leukemia LaboratoryStock and Other Ownership Interests: MLL Munich Leukemia Laboratory Shahram KordastiHonoraria: Beckman Coulter, GWT-TUD, Alexion PharmaceuticalsConsulting or Advisory Role: Syneos HealthResearch Funding: Celgene, Novartis Guillermo SanzHonoraria: CelgeneConsulting or Advisory Role: Abbvie, Celgene, Helsinn Healthcare, Janssen, Roche, Amgen, Boehringer Ingelheim, Novartis, TakedaSpeakers' Bureau: TakedaResearch Funding: CelgeneTravel, Accommodations, Expenses: Celgene, Takeda, Gilead Sciences, Roche Pharma AG Armando SantoroConsulting or Advisory Role: Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer AG, MSD, Sanofi, ArQuleSpeakers' Bureau: Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer AG, MSD Uwe PlatzbeckerHonoraria: Celgene/JazzConsulting or Advisory Role: Celgene/JazzResearch Funding: Amgen, Janssen, Novartis, BerGenBio, CelgenePatents, Royalties, Other Intellectual Property: part of a patent for a TFR-2 antibody (Rauner et al. Nature Metabolics 2019)Travel, Accommodations, Expenses: Celgene Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene Torsten HaferlachEmployment: MLL Munich Leukemia LaboratoryLeadership: MLL Munich Leukemia LaboratoryConsulting or Advisory Role: IlluminaNo other potential conflicts of interest were reported.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS., (© 2019 by The American Society of Hematology.)