Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.

Myelodysplastic syndromes (MDSs) are chronic and often progressive myeloid neoplasms associated with remarkable heterogeneity in the histomorphology and clinical course. Various somatic mutations are involved in the pathogenesis of MDS. Recently, mutations in a gene encoding a spliceosomal protein, SF3B1, were discovered in a distinct form of MDS with ring sideroblasts. Whole exome sequencing of 15 patients with myeloid neoplasms was performed, and somatic mutations in spliceosomal genes were identified.Sanger sequencing of 310 patients was performed to assess phenotype/genotype associations. To determine the functional effect of spliceosomal mutations, we evaluated pre-mRNA splicing profiles by RNA deep sequencing. We identified additional somatic mutations in spliceosomal genes, including SF3B1, U2AF1, and SRSF2. These mutations alter pre-mRNA splicing patterns. SF3B1 mutations are prevalent in low-risk MDS with ring sideroblasts, whereas U2AF1 and SRSF2 mutations are frequent in chronic myelomonocytic leukemia and advanced forms of MDS. SF3B1 mutations are associated with a favorable prognosis, whereas U2AF1 and SRSF2 mutations are predictive for shorter survival. IntroductionThe myelodysplastic syndromes (MDSs) are characterized by clonal hematopoiesis, a variety of chromosomal abnormalities, bone marrow (BM) failure, and a propensity for evolution to acute myeloid leukemia (AML). Because of their often protracted course, MDSs recapitulate the stages of acquisition of a malignant phenotype, thereby offering insights into leukemogenesis. Although, traditionally, histomorphology-based schemes have been applied to subclassify patients with MDS, 1,2 this approach is unlikely to be reflective of the underlying pathogenesis. Instead, a better molecular characterization of MDS on the genomic, epigenetic, and genetic levels probably more objectively diagnoses conditions, determines patients' prognosis and, based on the underlying molecular defects, directs the application of targeted therapies. The emerging realization of the molecular diversity of MDS parallels the clinical and phenotypic heterogeneity of this disease. Moreover, molecular defects have the potential to serve as biomarkers and probably are more suitable for the identification of therapy targets and responsiveness/refractoriness to treatment.The application of high-throughput molecular technologies, including high-density single nucleotide polymorphism arrays (SNP-As) 3 and new sequencing technologies 4,5 has led to the improved characterization of genomic lesions such as chromosomal aberrations and of somatic mutations affecting specific classes of genes, 6 including signal transducers (eg, CBL), 7-10 apoptotic genes (eg, TP53 and RAS), [11][12][13] genes involved in epigenetic regulation of DNA (eg, DNMT3A, IDH1/2, and TET2), [14][15][16][17][18] and histone modifiers (eg, EZH2, UTX, and ASXL1). [19][20][21][22][23][24] Although some mutations in these factors are activating, most are loss-of-function or hypomorphic mutations and affect bona fide t...

Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs

No abstract

• Recurrent hypomorphic cohesin defects and cohesin low expression were identified in a significant proportion of patients with MDS and AML.• Cohesin mutations likely represent secondary events in clonal hierarchy and contribute to clonal transformation.Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n 5 386), myeloproliferative neoplasms (MPNs) (n 5 55), MDS/MPNs (n 5 169), and AML (n 5 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deepsequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P 5 .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P 5 .017). (Blood.