According to the French-American-British (FAB) classification, 22 the patients were classified as follows: 31 cases of refractory anemia (RA), 8 cases of refractory anemia with ringed sideroblasts (RARS), 7 cases of refractory anemia with excess blasts (RAEB), 3 cases of refractory anemia with excess blasts in transformation (RAEBt), and 2 cases of chronic myelomonocytic leukemia (CMML). In this context, the objective of this work was to investigate the occurrence of the hotspot mutations E542, E545 and H1047 in PI3K, V617F in JAK2, ITDs and D835 in FLT3 and exon 12 mutations in NPM1 in MDS patients in a Brazilian population.ĭNA samples were obtained from bone marrow aspirates of 51 patients diagnosed with de novo MDS. Mutations in PI3K, JAK2, FLT3 and NPM1 have been described in cases of MDS however, additional studies are necessary to clarify their role in this disease. Furthermore, a point mutation in exon 20 of the FLT3 gene (FLT3-D835) has been described in a case of AML. According to Gale et al, 21 it is possible to identify 3 prognostic groups based in the presence or absence of FT元 and NPM1 mutations: good (FLT3-ITD − NPM1 +), intermediate (FLT3-ITD − NPM1 − or FLT3-ITD + NPM1 +), and poor prognosis (FLT3-ITD + NPM1 −). 20 Internal tandem duplications (ITDs) in FLT3 and NPM1 mutations are frequent events in the development of AML, and are associated with prognosis. NPM1 mutations often result in the predominant localization of the protein to the cytoplasm, leading to destabilization of p14ARF and to the inhibition of p53. 19 Nucleophosmin (NPM1) is a key regulator of hematopoesis that shuttles between the nucleus and cytoplasm. 18įMS-like tyrosine kinase 3 (FLT3) is a tyrosine kinase receptor that plays an important role in the proliferation and differentiation of hematopoietic progenitors. 5, 14- 17 One somatic mutation in the JAK2 gene (V617F) has been identified in myeloproliferative disorders such as polycythemia vera (PV) and myelofibrosis. 4, 5, 13 Hotspot mutations occur in exon 9 (E542 and E545) and in exon 20 (H1047), resulting in increased PI3K/Akt activity. 10- 12 Mutations in the catalytic subunit of PI3K are frequently observed in several cancers, including AML. The Phosphatidylinositol-3-kinase (PI3K) and Janus kinase 2 (JAK2) signaling pathways are involved in numerous cellular processes, such as proliferation, apoptosis and differentiation. 4- 6 The same occurs for liver adenomatosis, 7 Rubinstein-taybi syndrome 8 and hemochromatosis. 2, 3 The accumulation of genetic alterations is closely associated with the progression of MDS toward AML, and efforts are being made to determine the significance of various genetic aberrations in patients with MDS. 1 Low-risk MDS present high levels of intramedullar apoptosis, whereas high-risk MDS show a decrease in apoptosis, an increase in cell proliferation and a high frequency of evolution to AML. Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress to acute myeloid leukemia (AML).
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