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Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.

Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10−5, Shannon Index HR = 0.81, P = 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P = 6 × 10−6), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.

Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients, which we classified as causal (n = 21) or unknown significance (n = 7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. The median age was 69 years; most patients were men (79%). Only 9 patients (27%) had a family history of hematological malignancy, and 15 (46%) had a personal history of cytopenia years before MDS/AML diagnosis. Most patients had a normal karyotype (85%), and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n = 9) or azacitidine (n = 11) had an overall response rate of 100% or 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome.

TO THE EDITOR: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a rare aggressive malignancy in adults. BCP-ALL is frequently characterized by recurrent chromosomal translocations that deregulate proto-oncogenes or result in fusion genes encoding chimeric oncoproteins.[1][1] Gene

There is a Blood Commentary on this article in this issue.

Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.

International audience; Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML.

Background: MDS and AML are mostly found in elderly patients. However, even in this population there is increasing evidence of predisposing genetic conditions, which have been underdiagnosed so far. Identifying inherited predisposition to myeloid disorders can be crucial especially in the context of hematopoietic stem cell transplantation (HSCT). Germline mutations in the DEAD/H-box helicase gene DDX41 have been identified in families with multiple cases of MDS or AML but also in sporadic cases. We aimed to analyze the prevalence and clinical features of DDX41-related myeloid malignancies within an unselected cohort of pts diagnosed with MDS or AML (MDS/AML). Methods Between March 2017 and June 2018, mutation screening was performed in 842 consecutive pts with a diagnosis of MDS/AML in a single center at Hôpital Saint-Louis, Paris. DNA was obtained from bone marrow or peripheral blood. Targeted sequencing of all exons of a panel of 80 genes recurrently mutated in myeloid malignancies was performed using custom capture-based library preparation (Agilent SureSelect) and Illumina sequencing. Sanger sequencing was performed on selected pts' cultured skin fibroblasts to check for the putative germline origin of the variants. Results We identified a DDX41 gene variant in 36 unrelated pts (4% of 842). We focused on the 32 pts having at least one DDX41 variant with a variant allele frequency (VAF) ranging from 40 to 60% highly suggestive of a germline origin, which was subsequently confirmed in all available cases (N=7). Sixteen variants were classified as pathogenic or likely pathogenic based on major predicted changes in protein sequence while the 16 others were missense variants of unknown significance (VUS), which scored deleterious in most algorithms (Figure 1A). An additional, likely somatic DDX41 mutation (VAF < 40%) was present in 18 of 32 pts (56%). Overall, 22 pts could be unambiguously considered as having a DDX41-related malignancy based on the presence of a major disturbing mutation and/or a second DDX41 mutation, while 10 pts had a single VUS. Twenty-six variants were newly described, including a recurrent one, G173R found in 5 pts, all having a second DDX41 mutation. Median age of the 32 patients was 70 years (35-88). Only 4 pts (12%) had a familial history of hematologic disorders. According to revised WHO classification, 4 (12.5%) had MDS-MLD, 8 MDS-EB (25%), 12 AML (37.5%), 6 MDS/MPN (18.7%), one 5q syndrome and one aplastic anemia. Strikingly, 15/32 (47%) pts had a history of cytopenia several years before blastic evolution and the 5 pts with G173R presented with hypoplastic MDS or initially isolated cytopenias, suggesting a specific functional effect of this mutation. Karyotype was normal in 16 pts (44%), complex in one, 12 pts had an isolated abnormality, and three had cytogenetic failure. Additional driver mutations were identified in most (27/32,84%) pts (Figure 1B), but we noticed that they were less frequent and at lower VAF in pts having both germline and somatic DDX41 mutations as compared to pts with a single variant (median 1.5 vs 3 mutations, median VAF 7% vs 29.5%, p Seven low-risk MDS pts were untreated, 7 received ESA and 5 (71%) responded. Ten high-risk MDS/AML pts received a hypomethylating agent and 8 (80%) achieved hematological response. Nine AML pts received intensive chemotherapy, with a complete response rate of 100% (7/7, 2 ongoing) and 5 of them had HSCT, all of them being alive with tolerable toxicity. Five pts died, median OS was 87 months, and 2-y OS was 89%. No difference on OS was observed between single and double-DDX41 mutated pts. Conclusions: DDX41 germline variant carriers represent a significant part of MDS/AML pts, the vast majority presenting without familial history. The predicted change in protein and/or the presence of a second somatic mutation strongly support the causality of the germline variant in most pts. By contrast with previous reports, pts frequently presented a phase of cytopenia before overt malignancy. Finally, outcome regarding response to treatment and OS in this DDX41-mutated cohort appeared relatively favorable. Figure 1. Figure 1. Disclosures Peffault De Latour: Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Fenaux:Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), −7/7q (17.2%), and 11q− (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPα mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure.

Mutations of the ten eleven translocation 2 gene (TET2) have recently been reported in myelodysplastic syndrome and myeloproliferative neoplasms. We analyzed the incidence and prognostic value of TET2 point mutations and other genomic alterations by direct sequencing and single nucleotide polymorphism microarray analysis in 111 de novo acute myeloid leukemia, who had all achieved complete remission (CR). Mutations were observed in 19 (17%) of the 111 patients compared with 10 (27%) of 36 patients who had failed to achieve CR (P = .2). In the 111 patients who had achieved CR, TET2 alterations were only significantly associated with NPM1 mutations but not with other pretreatment characteristics. TET2 gene status was not significantly correlated with disease-free survival and overall survival, both in the entire cohort and in patients with normal karyotype.

Abstract 2533 Acute myeloid leukemia (AML) is a heterogeneous disease because of different leukemogenic mechanisms and variable response to antileukemic treatment. In addition to age and leukocytosis at diagnosis, cytogenetic abnormalities are key factors to assess prognosis. Several gene alterations such as those involving CEBPa, NPM1 and FTL3 have been identified and have improved the classification of AML. However, variability remains and cannot be completely explained. In this study, we performed SNP array analysis on a cohort of 128 AML patients in order to identify new genetic alterations and potential new candidate genes involved in leukemogenesis or disease progression. Patients were classified according to MRC cytogenetics (26 favourable; 77 intermediates, 15 adverse, 10 no informative caryotype). Patients were aged from 11 to 65 years and distributed across all French-American-British (FAB) classes except M3 (8 M0, 25 M1, 38 M2, 26 M4 and 11 M4Eo, 12 M5, 2 M6), Paired DNA was extracted from bone marrow aspirates obtained at diagnosis and after achieving complete remission (CR), and analyzed using Affymetrix Genome-Wide Human SNP Array 6.0 to distinguish acquired from constitutional genetic abnormalities. Copy number variations (CNA) were validated on a custom Agilent microarray (Human Genome CGH Microarray 105k). Data were analyzed using Affymetrix' Genotyping Console 3.0.2, Agilent's GeneSpring GX. Statistical analyses were executed using R version 12.1. The Cox proportional hazard regression model was used to relate genetic abnormalities to treatment outcome, with karyotype included as the second covariate. Time was censored at transplantation date if bone marrow transplantation was performed. We found 210 genomic abnormalities in 74 patients: 197 CNA and 13 copy neutral losses of heterozygosity (uniparental disomy or UPD), resulting in 1.6 abnormalities on average per patient (range 0 to 17). Among CNA, deletions were more frequent than gains (130 vs. 66). CNA spanned from 8kb to 191MB (median of gains 24MB, median of losses 2MB). 116 of them had not been detected by conventional cytogenetics. UPD spanned from 23MB to 150MB (median, 33 MB). Abnormalities were located over all chromosomes except for chromosome14 and were particularly frequent on chromosomes 2, 7, 11, 16, 17, and 21 (54% of all abnormalities). We defined 72 minimal common regions which were altered in at least 2 patients. Among the 43 common regions shorter than 5Mb, 16 contain at least one gene reported in AML or cancer. CNA and UPD were distributed across all FAB subtypes. Of note, 7 of 8 patients with AML M0 had 1 or more abnormalities. Among the 74 patients with CNA or UPD, 36 had an intermediate caryotype. We found no significant association of number of abnormalities with known gene alterations known to influence prognosis (i.e., CEBPa, FLT3itd or NPM). As expected, there were significantly more alterations in patients with a favourable or adverse caryotype (P=0.0045, Fisher's exact test). Furthermore, the number of genetic abnormalities was significantly associated to disease-free and to overall survival (P=0.010 and 0.0016, respectively). This remained significant in a multivariate analysis including karyotype (P=0.046 and 0.01, respectively) CNA or UPD was detected in 56% of AML patients who achieved remission of these 45% have intermediate cytogenetics. We identified 43 minimal common regions shorter than 5MB, which were altered in at least 2 patients and 37% of these regions involve genes previously reported in AML or cancer. Increased genomic alterations were significantly associated with favorable and adverse cytogenetics and with disease-free and overall survival. Prognostic significance of number of abnormalities remains significant after adjustment for cytogenetics. DNA SNP array analysis may be useful to better define prognostic subgroups in addition to conventional cytogenetics and may identify candidate genes implicated in leukemogenesis or disease progression. Disclosures: No relevant conflicts of interest to declare.

Abstract 163 In acute myeloid leukemia (AML), both cytogenetic and molecular abnormalities are strongly associated with prognosis. In particular, in cytogenetically normal AML (CN-AML), FLT3-ITD (internal tandem duplication) carries adverse prognostic factor whereas NPM1 or CEBPA mutations are associated with favorable outcome. Recently, mutations of the ten eleven translocation 2 gene (TET2) have been reported myeloid neoplasms. We evaluated the frequency and prognostic value of TET2 alterations, in a cohort of 111 de novo AML patients. We studied 111 patients aged between 15 years and 69 years with previously untreated de novo AML who had reached complete remission (CR) using intensive chemotherapy. 28 of them also received an allogenic bone marrow transplantation in first CR. Analysis of TET2 sequence variation was performed by direct sequencing of PCR products from 111 genomic DNA samples obtained at diagnosis. Frameshift and nonsense variations were all scored as mutation whereas missense mutations were retained when observed at diagnostic but absent in the CR paired sample obtained. Previously identified single nucleotide polymorphisms (SNP) were not considered. TET2 anomalies were numbered according to Genebank reference FM992369. Paired diagnosis and CR genomic DNAs were analyzed using Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Data were analyzed using Gene Chip Genotyping Console 3.0.2 and Partek Genomics Suite (www.partek.com/). Comparisons were made by Fisher's exact test for binary variables and the Mann-Whitney‘s test for continuous variables. Disease Free Survival (DFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Comparisons regarding DFS and OS were performed with the log-rank test. 24 acquired TET2 mutations were observed in 19 of the 111 (17%) de novo AML patients, suggesting the alteration of the two TET2 alleles in 5 patients. They included 21 different events: 6 frameshift, 7 non-sense and 11 missense mutations. Four of the missense mutations were located in conserved regions and 7 outside. All of them were detected in the diagnostic sample but were absent in the paired remission sample. Except for two missense mutations (S282F, T492S) both detected in two patients, no recurrent TET2 mutation was observed. Acquired mutations were spread over all exons. No case of uniparental disomy (UPD) was observed and only one patient presented a small deletion of 60Kb in the TET2 gene locus without TET2 mutation. No significant difference was observed between patients with or without TET2 alterations for gender, age, hemoglobin level, platelet count, FAB subtypes distribution and cytogenetics according to MRC classification, but there was a trend for higher WBC count in patients with TET2 alteration. No significant association was observed between TET2 mutations and FLT3 or CEBPA alterations. However, TET2 alterations were significantly associated with NPM1 mutations (p=0.032). In the entire patient cohort, no difference in DFS or OS was seen between patients with and without TET2 alteration. However, a significantly worse DFS was observed for patients presenting TET2 mutations within the subgroup of patients with NPM1 mutations (3y-DFS: 0% vs 66.4%, 95% CI [45.6–87.2], p=0.008) Considering both the favorable prognosis of NPM1 mutations without FLT3-ITD in CN-AML and the absence of clear association between FLT3-ITD and TET2 alterations in this study, prognostic value of the genotype characterized by NPM1 mutation without FLT3-ITD or TET2 alteration (NPM1+FLT3-ITD-TET2-) was compared to other patients within CN-AML group (N=54). NPM1+FLT3-ITD-TET2- patients showed a significantly better DFS and OS compared to other patients in CN-AML group (3y-DFS: 82.1%, 95% CI [59.1–100] vs 37.3%, 95% CI [20.2–54.3], p=0.01; 3y-OS: 80.8%, 95% CI [56.1–100] vs 42.3%, 95% CI [23.3–61.3], p=0.04). In conclusion, we observed point mutations of TET2 in 17% of patients, whereas TET2 deletion or UPD are very rare. In our study, TET2 mutations were clearly associated with NPM1 mutations and carried a negative prognostic impact in this subgroup. Screening for TET2 mutations may improve the characterization of CN-AML and help to identify within the low-risk subgroup with NPM1 mutation and without FLT3-ITD, patients at high risk of relapse. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Abstract 975 Fanconi anemia (FA) is a rare genetic condition characterized by congenital abnormalities, chromosome fragility, progressive bone marrow failure during childhood, and cancer susceptibility. FA patients experience a high risk to develop myelodysplasia (MDS) and secondary-type acute myeloid leukemia (AML) during their teens or in young adulthood. Severity of the cytopenia, excess of blast cells and presence of a cytogenetic clone in the bone marrow are usual criteria to undertake hematopoietic stem cell transplantation. In order to investigate the pattern of chromosomal and genomic abnormalities during bone marrow progression in FA and their association to MDS/AML, we analyzed bone marrow samples from FA patients using a wide panel of chromosomal and molecular techniques including DNA microarrays and oncogene sequencing. This series of FA patients was enriched in patients older than 18 year-old and/or with morphological or karyotypic abnormalities on the follow up BM aspirate. 57 FA patients were included, aged 4 to 57 yo (median 18); FA groups were FA-A (n=49), FA-G (n=1), FA-D2 (n=1), FA-D1 (n=1) and undertermined (n=5). Bone marrow morphology was hypoplastic/aplastic anemia (n=20), MDS (n=18, mainly RCMD and RAEB according to the WHO 2008 classification), AML (n=11), or no abnormality except the usual mild dyserythropoiesis of FA (n=8). Bone marrow samples were analyzed by karyotype, FISH, high density array-CGH and/or SNP-arrays with respect to the paired fibroblast DNAs, and by sequencing of selected oncogenes and tumor suppressor genes. A specific pattern of genomic abnormalities due to unbalanced translocations was found in the 29 MDS/AML, which included 1q+ (44.8%), 3q+ (41.3%), -7/7q (17.2%), and 11q- (13.8%). Moreover, cryptic abnormalities (translocations, deletions or mutations) of the RUNX1/AML1 gene were evidenced for the first time in FA, in 6 out of the 29 patients with MDS or AML (20.7%). By contrast, mutations of FLT3-ITD, MLL-ITD, and N-RAS, but not TP53, CBL, TET2, CEBPa, NPM1, and FLT3-TKD, were rarely found. Frequent homozygosity regions were evidenced by SNP-array in 11 patients, but the analysis of the paired fibroblast DNA and the constitutional FANC mutations demonstrated that they were not related to somatic copy-neutral loss of heterozygosity but to consanguinity. Importantly, the RUNX1/AML1 and other chromosomal/genomic abnormalities were found at the MDS and AML stages only, except for 1q+ which could be found at any stages including normal bone marrow morphology. In our experience 1q+ does not predict systematically a transformation into MDS/AML in the following years. These data have important implications, not only for the cytogenetic staging of the bone marrow cells in FA patients with an impact for therapeutic managing, but also as a basis to investigate the multistep clonal selection and related oncogenesis in patients with hypoplastic bone marrow and genomic instability, with potential relevance for non-FA patients. Disclosures: Gluckman: Cord-use: Membership on an entity's Board of Directors or advisory committees.