From this analysis, we identified a novel case of a donor-derived myelodysplastic syndrome in an HSCT recipient that is consistent with clonal evolution of TET2-mutated clonal hematopoiesis of indeterminate potential (CHIP) within the donor.
Another significant advance in MDS pathogenesis research is the recent identification of mutations in genes encoding transcription factors implicated in hematopoiesis and proteins involved in splicing (SF3B1), methylation (DNMT3A), regulation of methylation (TET2 and IDH), DNA conformation (EZH2 and ASXL1) and differentiation (N- and K-RAS).
Genetic predispositions to myeloid malignancies can be classified into three categories: familial cancer syndromes associated with increased risk of various malignancies including myelodysplasia and acute myeloid leukemia such as Li-Fraumeni syndrome and constitutional mismatch repair deficiency (CMMRD); germline mutations conferring a specific increased risk of myelodysplastic syndrome and acute myeloid leukemia such as mutations in ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes; and finally primarily pediatric inherited bone marrow failure syndromes such as Fanconi anemia, dyskeratosis congenita, severe congenital neutropenia, Shwachman-Diamond syndrome and Diamond Blackfan anemia.
These data suggest ASXL1 mutations might results in dominance of the mutant clone in Chinese with MDS whereas EZH2 mutations might predict an increased risk of transformation to AML.
Ring sideroblasts (RS) emerge as result of aberrant erythroid differentiation leading to excessive mitochondrial iron accumulation, a characteristic feature for myelodysplastic syndromes (MDS) with mutations in the spliceosome gene SF3B1.
Contrary to previous reports, we found no association between TET2 mutations and HMA treatment response (40% vs 41%; P = 0.9), even in the absence of ASXL1 mutations (P = 0.4).We conclude that ASXL1 mutations in MDS predict inferior response to treatment with both HMAs and LEN; response to LEN was also compromised by U2AF1 mutations and high risk karyotype; SF3B1 mutations identified patients likely to respond to LEN.
A 61-year-old woman with NK-cell deficiency and GATA-2-associated myelodysplastic syndrome, status post-recent allogeneic HSCT (Day +58), presented with 3 days of acute-onset severe back pain, muscle cramps, and increasingly dark urine.
Recent studies are shedding light on the molecular basis of myelodysplasia and how mutations and epimutations can induce and promote this neoplastic process through aberrant transcription factor function (RUNX1, ETV6, TP53), kinase signalling (FLT3, NRAS, KIT, CBL) and epigenetic deregulation (TET2, IDH1/2, DNMT3A, EZH2, ASXL1, SF3B1, U2AF1, SRSF2, ZRSR2).
Various heteroallelic GATA2 gene mutations are associated with a variety of hematological neoplasms, including myelodysplastic syndromes and leukemias.
For the first time, we also detected TET2 mutations in BMMΦs from MDS and CMML patients and assayed their effects on LPS responses, including their potential influence on human IL-6 expression.
GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia.
U2AF1 is frequently mutated in myeloid hematopoietic malignancies, especially in myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL).
To identify acquired somatic mutations associated with myeloid transformation in patients with GATA2 mutations, we sequenced the region of the ASXL1 gene previously associated with transformation from myelodysplasia to myeloid leukemia.
This provides potential avenues to regulate TET2 function in the context of myeloproliferative disorders and myelodysplastic syndromes associated with the JAK2<sup>V617F</sup>-activating mutation.<i>This article is highlighted in the In This Issue feature, p. 681</i>.
Given that mRNA splicing and nuclear export are coordinated processes, we hypothesised that SF3B1 mutation might also affect export of certain mRNAs and that this may represent a targetable pathway for the treatment of SF3B1-mutant MDS.
In 2011, whole-exome sequencing studies showed recurrent somatic mutations of SF3B1 and other genes of the RNA splicing machinery in patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm.