Jurnal Internasional Defisiensi TET2 menyebabkan ekspansi klonal tergantung faktor sel dari progenitor erythroid disfungsional
Myelodysplastic syndromes (MDSs) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis. Anemia is defining cytopenia of MDS patients, but the molecular mechanism for dyserythropoiesis in MDSs remains fully defined. Recent research has revealed that mutation of heterozygous function loss from DNA oxygenated TET2 is 1 of the most common mutations in MDS and that TET2 deficiency interferes with erythroid differentiation. However, the mechanistic insight into TET2's role in irregular erythropoiesis is not fully determined. Here, we show that TET2 deficiency initially leads to stem cell factors (SCF) – independent hyperproliferation and impaired cell erythroid colonization (CFU-E) cell differentiation, which is reversed by c-Kit inhibitors. We further point out that this is because an increase in c-Kit phosphorylation is accompanied by a decrease in the expression of SHP-1 phosphatase, a negative regulator of c-Kit. In the next stage, TET2 deficiency causes accumulation of the progenitor population, which shows the characteristics of normal surface CFU-E cell markers but is functionally different. In contrast to normal CFU-E cells that only require erythropoietin (EPO) for proliferation, this abnormal ancestor requires SCF and EPO and shows a disruption of differentiation. We call this population progenitor cells “CFU-E markers”. We further show that AXL expression increases in cell markers CFU-E and that increased AXL expression causes increased AKT and ERK activation. In addition, changes in cell proliferation and differentiation in CFU-E markers were partially saved by AXL inhibitors. Our findings document an important role for TET2 in erythropoiesis and have found previously unknown mechanisms where TET2 deficiencies contribute to ineffective erythropoiesis.