Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis
Qi Zhang, … , Yu Liu, Chong Chen
Qi Zhang, … , Yu Liu, Chong Chen
Published February 8, 2022
Citation Information: JCI Insight. 2022;7(3):e153768. https://doi.org/10.1172/jci.insight.153768.
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Research Article Genetics Hematology

Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis

Abstract

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.

Authors

Qi Zhang, Lei Zhao, Yi Yang, Shujun Li, Yu Liu, Chong Chen

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Figure 4

KDM5D loss promotes tumorigenesis and increased DNA damage.

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KDM5D loss promotes tumorigenesis and increased DNA damage. (A) Venn di...
(A) Venn diagram showing the enrichment of the significantly downregulated genes in mLOY AML patients (top 200) and AML mice. (B and C) The expression levels of KDM5D in mLOY AML patients with AML1-ETO (B, n = 5; C, n = 3) and other AML1-ETO+ patients (B, n = 4; C, n = 3) in 2 AML cohorts (TARGET AML and BEAT AML), from analysis of The Cancer Genome Atlas data. *P < 0.05, **P < 0.01 (2-tailed t test). (D) Kaplan-Meier tumor-free survival curve of recipient mice with sgScr; AML1-ETO and sgKdm5d; AML1-ETO AML cells (n = 6). *P < 0.05 (log-rank test). (E) Left: Representative immunofluorescence images of γH2AX foci in sgScr and sgKdm5d HSPCs. Scale bars: 10 μm. Red, γH2AX; blue, DAPI-labeled DNA. Right: Plot of γH2AX foci per cell, shown as the mean ± SD. ****P < 0.0001 (2-tailed Mann-Whitney test). (F) Left: Representative images of comet assay of sgScr and sgKdm5d HSPCs. Scale bars: 50 μm. Right: Plot of comet assay of sgScr and sgKdm5d HSPCs. The tail moment is shown as the mean ± SD. ****P < 0.0001 (2-tailed Mann-Whitney test). (G) Left: Representative images of comet assay of sgSsty1-sgCas9 HSPCs with truncated-Kdm5d overexpression (bottom, the truncated KDM5D is a 659–amino acid protein consisting of aa 1–695) and vector only (top) was used as a negative control. Scale bars: 50 μm. Right: Plot of comet assay of sgSsty1-sgCas9 HSPCs with truncated-Kdm5d overexpression and vector only. The tail moment is shown as the mean ± SD. ****P < 0.0001 (2-tailed Mann-Whitney test). (H) Left: Representative images of comet assay of sgSsty2-sgCas9 HSPCs with truncated-Kdm5d overexpression (bottom) and vector only (top). Scale bars: 50 μm. Right: Plot of comet assay of sgSsty2-sgCas9 HSPCs with truncated-Kdm5d overexpression and vector only. The tail moment is shown as the mean ± SD. ****P < 0.0001 (2-tailed Mann-Whitney test).