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SF3B1 is a core component of the mRNA splicing machinery and frequently mutated in myeloid neoplasms with myelodysplasia, particularly in those characterized by the presence of increased ring sideroblasts. Deregulated RNA splicing is implicated in the pathogenesis of SF3B1-mutated neoplasms, but the exact mechanism by which the SF3B1 mutation is associated with myelodysplasia and the increased ring sideroblasts formation is still unknown. We investigated the functional role of SF3B1 in normal hematopoiesis utilizing Sf3b1 heterozygous-deficient mice. Sf3b1+/− mice had a significantly reduced number of hematopoietic stem cells (CD34−cKit+ScaI+Lin− cells or CD34−KSL cells) compared with Sf3b1+/+ mice, but hematopoiesis was grossly normal in Sf3b1+/− mice. When transplanted competitively with Sf3b1+/+ bone marrow cells, Sf3b1+/− stem cells showed compromised reconstitution capacity in lethally irradiated mice. There was no increase in the number of ring sideroblasts or evidence of myeloid dysplasia in Sf3b1+/− mice. These data suggest that SF3B1 plays an important role in the regulation of hematopoietic stem cells, whereas SF3B1 haploinsufficiency itself is not associated with the myelodysplastic syndrome phenotype with ring sideroblasts. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which investigates the recurrent genetic defects on chromosome 7q in myeloid neoplasms and on other comprehensive molecular screen of chromosome 7 (chr7).

High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients. [ABSTRACT FROM AUTHOR]

The article presents a study which suggests that dysfunction of EED mutants might be involved in the pathogenesis of myeloid disorders. It explores the identification of the catalytic subunit of polycomb recessive complex 2 (PRC2) in the subsets of myeloid disorders including myelodysplastic syndrome (MDS). The data gathered in the study suggest that various types of defective EED mutations contribute to the MDS pathogenesis.

The unbalanced translocation, der(1;7)(q10;p10), is one of the characteristic cytogenetic abnormalities found in myelodysplastic syndromes (MDS) and other myeloid neoplasms. Although described frequently with very poor clinical outcome and possible relationship with monosomy 7 or 7q- (−7/7q-), this recurrent cytogenetic abnormality has not been explored fully. Here we analyzed retrospectively 77 cases with der(1;7)(q10;p10) in terms of their clinical and cytogenetic features, comparing with other 46 adult −7/7q- cases without der(1;7)(q10;p10). In contrast with other −7/7q- cases, where the abnormality tends to be found in one or more partial karyotypes, der(1;7)(q10;p10) represents the abnormality common to all the abnormal clones and usually appears as a sole chromosomal abnormality during the entire clinical courses, or if not, is accompanied only by a limited number and variety of additional abnormalities, mostly trisomy 8 and/or loss of 20q. der(1;7)(q10;p10)-positive MDS cases showed lower blast counts (P<0.0001) and higher hemoglobin concentrations (P<0.0075) at diagnosis and slower progression to acute myeloid leukemia (P=0.0043) than other −7/7q- cases. der(1;7)(q10;p10) cases showed significantly better clinical outcome than other −7/7q cases (P<0.0001). In conclusion, der(1;7)(q10;p10) defines a discrete entity among myeloid neoplasms, showing unique clinical and cytogenetic characteristics.Leukemia (2007) 21, 992–997. doi:10.1038/sj.leu.2404619; published online 22 February 2007 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the pathogenesis and high frequencies of novel splicing-factor mutations juvenile myelomonocytic leukemia (JMML).

A letter to the editor is presented regarding the study on the incidence and prognosis of isocitrate dehydrogenase gene (IDH1) and IDH2 mutations in pediatric myeloid malignancies.

A letter to the editor is presented regarding the mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) in a series of cases with myelodysplastic syndrome (MDS).

A letter to the editor is presented related to CBL mutations in Juvenile myelomonocytic leukemia.