On May 12, 2020, the top international journal, Cell Stem Cell, published an important original work from Prof. Haojian Zhang’s laboratory in our hospital, entitled "Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis". Prof. Haojian Zhang joined our hospital in 2016, and was the corresponding author of this paper. Graduate student of our hospital, Yicun Li, was the co-first author (second place).
Acute myeloid leukemia (AML) is an aggressive and fatal hematologic malignancy characterized by uncontrolled expansion of poorly differentiated myeloid cells. AML originates from leukemia stem cells (LSCs) that are transformed from normal hematopoietic stem/progenitor cells (HSPCs) with accumulation of acquired genetic and epigenetic changes. LSCs are responsible for leukemia initiation, progression and relapse. Thus, it is critical to explore distinct mechanisms during leukemogenesis at a molecular level for a better understanding of AML pathogenesis that will lead to the development of potentially effective therapeutic strategies. In this study, they show that expression of m6A demethylase ALKBH5 is regulated by chromatin state alteration during leukemogenesis of human acute myeloid leukemia (AML), and ALKBH5 is required for maintaining leukemia stem cell (LSC) function, but is dispensable for normal hematopoiesis. Mechanistically, KDM4C regulates ALKBH5 expression via increasing chromatin accessibility of ALKBH5 locus, by reducing H3K9me3 levels and promoting recruitment of MYB and Pol II. Moreover, ALKBH5 affects mRNA stability of receptor tyrosine kinase AXL in an m6A-dependent way. Thus, our findings link chromatin state dynamics with expression regulation of m6A modifiers, and uncover a selective and critical role of ALKBH5 in AML that might act as a therapeutic target of specific targeting LSCs.
In the past few years, Prof. Haojian Zhang has worked on exploring the unique molecular mechanisms of leukemia stem cell maintenance, and achieved a series of original findings that were published in the international top journals, including Cell Stem Cell, Nature Genetics, and Blood. This work was supported by the National Key Research and Development Program of China, and the National Natural Science Foundation of China.
