Blood: HHEX and Mutant ASXL1 work together to promote myelin transformation

The Additional Sex Combs-like 1, ASXL1 encodes a chromatin binding protein, an epigenetic regulatory factor that mutates frequently in myelin tumorsRecent analysis of mutant ASXL1 condition knock-in (ASXL1-MT-KI) mice showed that ASXL1-MT alone was not sufficient for bone marrow conversionIn previous studies, Takeda et alobtained ASXL1-MT-KI hematopoietic cells through retrovirus-mediated insertion mutations, which showed susceptibility to conversion into myeloid leukemia cellsIn further studies, Takeda et alfound that hematopoietic stem cell expression homologous box (HHEX) gene is also one of the common sites of retrovirus integrationAs a result, Takeda and others are studying the potential collaboration between ASXL1-MT and HHEX in the development of myeloid leukemiaIt was found that the expression of HHEX enhanced the proliferation of HSCs expressing ASXL1-MT by inhibiting apoptosis and blocking differentiation, but only had a mild effect on normal HSPCsIn addition, ASXL1-MT and HHEX accelerate the occurrence of RUNX1-ETO9a and FLT3-ITD leukemiaOn the contrary, HHEX depletion can significantly delay the formation of leukemia in the clone-forming activity and expression of ASXL1-MT leukemia cellsOn a mechanism, the researchers found that MYB and ETV5 were downstream targets for ASXL1-MT and HHEX through transcription groups and CHIP-seq analysisThe researchers also found that the expression of ASXL1-MT increased the combination of HHEX with the startup sub-point of MYB or ETV5 by reducing H2AK119ubMYB or ETV5 deficiency can induce apoptosis or differentiation of leukemia cells expressing ASXL1-MT respectivelyIn addition, the ectopic expression of MYB or ETV5 reverses the decrease in the activity of the leukemia cell colony of the missing expression of HHEX, ASXL1-MTAll in all, this study suggests that the HHEX-MYB/ETV5 axis has a role in promoting myelin transformation in asXL1 mutation leukemia precursor cells