Jurnal Internasional Erythropoiesis yang tidak efektif dari defisiensi TET2

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Jurnal Internasional Erythropoiesis yang tidak efektif dari defisiensi TET2

Studies by Qu et al 1 in this edition Blood provides new mechanistic insights into ineffective erythropoiesis from TET2 deficiency including erythroid-selective colonization units (CFU -E) hyperproliferation, increased expression of KIT and AXL [1945911] and salvage by KIT and AXL inhibitors of choked late stage erythropoiesis.

(De) DNA methylation at loci and specific elements can guide growth hematopoietic ancestors cell and differentiation. 2 If it is not balanced, hypermetylation can suppress tumor suppression, whereas hypomethylation can contribute to genome instability. 2 3 TET-1, TET -2, and TET-3 proteins function as active (II) oxygen, 2-oxoglutarat depending on mediating DNA demethylation. This involves the oxidation of 5mC to 5hmC, 5fC, and 5caC. Seminal clinical studies have been associated with removal and / or mutation in TET2 (4q24) with myelodysplastic syndrome (MDS), myeloproliferative neoplasms, chronic myelomonocytic leukemia, and acute myeloid leukemia. 4 TET2 mutations are generally clustered in the catalytic region (residue). 1104-1478 and 1845-2002) with missense mutations which usually reduce catalytic activity, 5hmC level, and DNA methylation profile. Such TET2 mutations are also associated with B-cell lymphogenesis 2 3 and certain T cell leukemia. 2 3 TET-1 and TET-3, by contrast, rarely mutate in hematological malignancies.

MDS, myeloproliferative neoplasms, and chronic myelomonocytic leukemia also often show anemia due to ineffective erythropoiesis, [19659019] 5 6 [19659003] a feature that raises a central question regarding the effects given by TET2 during normal erythropoiesis. Short hairpin RNA (shRNA), a study of loss-of-function (LOF) now reported by Qu et al 1 focused on this question and contributed several new findings. Previous studies using Tet2 KO (KO) rats, and ex vivo human erythroid progenitor (EPC) cells determined that TET2 loss-function (LOF) impaired erythroid differentiation. 2 3 Qu et al now revealed that TET2 LOF mediated by TET2 selectively promoted hyperexpansion from the EPC group similar to CFU-E. The hyperexpansion occurs between ∼20% of EPC; depends sharply on stem cell factors (SCF) and erythropoietin; including low glucophorin A 19459007 phenotype; and continues for 1 month. In comparison, there was no similar hyperproliferative effect of TET2 LOF observed between later erythroblastic progenitors. Because it correlates with SCF dependence from disregulated progenitors such as CFU-E, TET2 LOF causes estimates of a doubling in the level of KIT, along with a parallel decrease in the level of SHP1 tyrosine phosphatase, a negative effector of KIT. Activation of SHP1, however, is not assessed. Furthermore, inhibition of KIT by ST157 reverses the TET2 LOF EPC phenotype and increases final erythroblast differentiation.

As isolated from ex vivo cultures, d6 CFU-E and d13 TET2 LOF CFU-E are also compared. On d13 TET2 LOF CFU-E, RNA sequencing revealed> 10 times the expression of AXL tyrosine kinase receptors . AXL along with TYRO3 and MER are TAM receptors that share GAS6 as a general ligand. 7 AXL is also the target of the drug for acute myeloid leukemia. 7 Interestingly, and as studied by Qu et al. , the hyperproliferative and attenuated differentiation phenotypes of CFU-E LOF TET2 were partially reversed by AXL R428 inhibitors. Compounds [1945910] Axl – / – Mer – / – KO mice, the development of the same attenuated (pro) erythroblast was observed. 8 This effect, however, was not exhibited by a single mouse [1945910] Axl – / – KO. In d6 normal CFU-E vs. d13 TET2 LOF CFU-E, Qu et al also analyzed the effects of shRNA-mediated TET2 knockdown on DNA methylation. On TET2 LOF CFU-E, the 5mC level increases and the 5m level decreases. In addition, the area of ​​14414 from the AXL promoter was proven to have methylated differently due to TET2 knockdown, but to 5hmC (and not 5mC). This 5hmc phenomenon, however, is not without precedent and has been observed for selected DNA loci in TET2 KO embryonic stem cells. In future studies, the possibility of alternative mechanisms underlying the increase in AXL expression of TET2 LOF can now be considered, including the possible effects on genes involved in AXL activation . In MDS patients with TET2 mutations, the possibility of increasing AXL expression in EPC will also be meaningful to assess.

Overall, recent studies by Qu et al provide new insights into some specific effects of TET2 deficiency on ineffective erythropoiesis and give rise question. significant interest. Does SCF-dependent hyperproliferation of TET2 LOF CFU-E mechanically involve increased KIT expression, or increased KIT expression may be an indirect consequence of other TET2 target actions governing self-renewal CFU-E? Outside of SHP1, what signal transduction factors might be affected by TET2 LOF that contribute to increased KIT signaling? What mechanisms depend on TET2 increasing expression and AXL are similarly regulated by 5mC DNA methylation inhibitors? To what extent is R428 specific to AXL (and at the dose used)? And what are the candidates for endogenous sources of AXL ligands (for example, blood island macrophages)? Insights, and the EPC stage model specification system produced by Qu et al, must function well in providing workable breakthroughs to critically assess this problem.

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