Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis
Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis
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DOI：
10.1172/jci.insight.153768
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发表时间：
2022
期刊：
影响因子：
8
通讯作者：
Chen Chong
中科院分区：
文献类型：
--
作者：
Zhang Qi;Zhao Lei;Yang Yi;Li Shujun;Liu Yu;Chen Chong
Mosaic loss of chromosome Y (mLOY) in blood cells is one of the most frequent chromosome .alterations in adult males. It is strongly associated with clonal hematopoiesis, hematopoietic .malignancies, and other hematopoietic and nonhematopoietic diseases. However, whether there .is a causal relationship between mLOY and human diseases is unknown. Here, we generated .mLOY in murine hematopoietic stem and progenitor cells (HSPCs) with CRISPR/Cas9 genome .editing. We found that mLOY led to dramatically increased DNA damage in HSPCs. Interestingly, .HSPCs with mLOY displayed significantly enhanced reconstitution capacity and gave rise to clonal .hematopoiesis in vivo. mLOY, which is associated with AML1-ETO translocation and p53 defects .in patients with acute myeloid leukemia (AML), promoted AML in mice. Mechanistically, loss .of KDM5D, a chromosome Y–specific histone 3 lysine 4 demethylase in both humans and mice, .partially recapitulated mLOY in DNA damage and leukemogenesis. Thus, our study validates mLOY .as a functional driver for clonal hematopoiesis and leukemogenesis.
