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

Large granular lymphocytic leukemia (LGLL) represents a clonal/oligoclonal lymphoproliferation of cytotoxic T and natural killer cells often associated with STAT3 mutations. When symptomatic, due to mostly anemia and neutropenia, therapy choices are often empirically-based, because only few clinical trials and systematic studies have been performed. Incorporating new molecular and flow cytometry parameters, we identified 204 patients fulfilling uniform criteria for LGLL diagnoses and analyzed clinical course with median follow-up of 36 months, including responses to treatments. While selection of initial treatment was dictated by clinical features, the initial responses, as well as overall responses to methotrexate (MTX), cyclosporine (CsA), and cyclophosphamide (CTX), were similar at 40-50% across drugs. Sequential use of these drugs resulted in responses in most cases: only 10-20% required salvage therapies such as ATG, Campath, tofacitinib, splenectomy or abatacept. MTX yielded the most durable responses. STAT3-mutated patients required therapy more frequently and had better overall survival.

Key Points STAT3+ T cells are found not only in detected concomitant LGL-BMFs, but in cases in which an LGL expansion was not suspected. Transformation via acquisition of a somatic mutation in T cells may be a mechanism of immune, mainly hypoplastic, bone marrow failure.