Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias
ABSTRACT The impact of ten-eleven-translocation 2 (TET2) mutations on response to azacitidine (AZA) in MDS has not been reported. We sequenced the TET2 gene in 86 MDS and acute myeloid leukemia (AML) with 20-30% blasts treated by AZA, that is disease categories wherein this drug is approved by Food and Drug Administration (FDA). Thirteen patients (15%) carried TET2 mutations. Patients with mutated and wild-type (WT) TET2 had mostly comparable pretreatment characteristics, except for lower hemoglobin, better cytogenetic risk and longer MDS duration before AZA in TET2 mutated patients (P=0.03, P=0.047 and P=0.048, respectively). The response rate (including hematological improvement) was 82% in MUT versus 45% in WT patients (P=0.007). Mutated TET2 (P=0.04) and favorable cytogenetic risk (intermediate risk: P=0.04, poor risk: P=0.048 compared with good risk) independently predicted a higher response rate. Response duration and overall survival were, however, comparable in the MUT and WT groups. In higher risk MDS and AML with low blast count, TET2 status may be a genetic predictor of response to AZA, independently of karyotype.
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ABSTRACT: Myelodysplastic syndromes (MDS) are a group of clonal disorders arising from hematopoietic stem cells generally characterized by inefficient hematopoiesis, dysplasia in one or more myeloid cell lineages, and variable degrees of cytopenias. Most MDS patients are diagnosed in their late 60s to early 70s. The estimated incidence of MDS in the United States and in Europe are 4.3 and 1.8 per 100,000 individuals per year, respectively with lower rates reported in some Asian countries and less well estimated in other parts of the world. Evolution to acute myeloid leukemia can occur in 10-15% of MDS patients. Three drugs are currently approved for the treatment of patients with MDS: immunomodulatory agents (lenalidomide), and hypomethylating therapy [HMT (decitabine and 5-azacytidine)]. All patients will eventually lose their response to therapy, and the survival outcome of MDS patients is poor (median survival of 4.5 months) especially for patients who fail (refractory/relapsed) HMT. The only potential curative treatment for MDS is hematopoietic cell transplantation. Genomic/chromosomal instability and various mechanisms contribute to the pathogenesis and prognosis of the disease. High throughput genetic technologies like single nucleotide polymorphism array analysis and next generation sequencing technologies have uncovered novel genetic alterations and increased our knowledge of MDS pathogenesis. We will review various genetic and non-genetic causes that are involved in the pathogenesis of MDS.12/2014; 49(4):216-27. DOI:10.5045/br.2014.49.4.216
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ABSTRACT: Myelodysplastic syndromes (MDS) are a heterogeneous cluster of clonal hematopoietic neoplasms manifested by peripheral cytopenias, lineage dysplasia, and a predisposition to acute myeloid leukemia. The pathophysiology of MDS has not been well illustrated. Nevertheless, studies have implicated the MDS phenotype in a broad spectrum of genetic abnormalities. In addition to the known numerical and structural chromosomal abnormalities, with novel genomic sequencing technologies, approximately 80% of MDS patients have been shown to harbor somatic or acquired gene mutations. The mutations have been found to be related to RNA slicing, transcription regulation, DNA methylation, histone modification, DNA repair/tumor suppressor, signal transduction, and the cohesion complex. The clinical significance of the majority of genetic events has been validated based on a large cohort study that identified mutations as predictors for risk stratification in MDS patients and biomarkers for potential targeted therapies. In this review, we describe all novel key mutations in MDS and their significance in pathophysiology and clinical practice. Copyright © 2014 Elsevier Ltd. All rights reserved.Leukemia Research 11/2014; 39(1). DOI:10.1016/j.leukres.2014.10.006 · 2.69 Impact Factor
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ABSTRACT: The Ten-ElevenTranslocation-2 (TET2) gene encodes a member of the TET family of DNA methylcytosine oxidases that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to initiate the demethylation of DNA within genomic CpG islands. Somatic loss-of-function mutations of TET2 are frequently observed in human myelodysplastic syndrome (MDS), which is a clonal malignancy characterized by dysplastic changes of developing blood cell progenitors leading to ineffective hematopoiesis. We used genome editing technology to disrupt the zebrafish Tet2 catalytic domain. tet2 m/m zebrafish exhibited normal embryonic and larval hematopoiesis, but developed progressive clonal myelodysplasia as they aged, culminating in MDS at 24 months of age, with dysplasia of myeloid progenitor cells and anemia with abnormal circulating erythrocytes. The resultant tet2 m/m mutant zebrafish lines show decreased levels of 5hmC in hematopoietic cells of the kidney marrow, but not in other cell types, most likely reflecting the ability of other Tet family members to provide this enzymatic activity in non-hematopoietic tissues but not in hematopoietic cells. tet2 m/m are viable and fertile, providing an ideal model to dissect altered pathways in hematopoietic cells and for small molecule screens in embryos to identify compounds with specific activity against tet2 mutant cells. Copyright © 2014, American Society for Microbiology. All Rights Reserved.Molecular and Cellular Biology 12/2014; 35(5). DOI:10.1128/MCB.00971-14 · 5.04 Impact Factor