Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis
Qi Zhang, Lei Zhao, Yi Yang, Shujun Li, Yu Liu, Chong Chen
Qi Zhang, Lei Zhao, Yi Yang, Shujun Li, Yu Liu, Chong Chen
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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 2

mLOY collaborates with AML1-ETO to promote leukemogenesis.

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mLOY collaborates with AML1-ETO to promote leukemogenesis. (A) Schematic...
(A) Schematic of mLOY AML mouse model. HSPCs from male Trp53–/–; Cas9 mice were infected with mCherry-linked Y-chromosome-targeting sgRNA (sgSsty1 and sgSsty2)-sgCas9 and GFP-linked AML1-ETO and then transplanted into sublethally irradiated female recipient mice, with sgScr-sgCas9 as a negative control. (B) White blood cell (WBC) counts and red blood cell (RBC) counts of recipient mice at 7 weeks after transplantation with sgScr-sgCas9; AML1-ETO, sgSsty1-sgCas9; AML1-ETO, and sgSsty2-sgCas9; AML1-ETO HSPCs. WBC counts greater than 40 × 109/L are above the gray dotted line and those less than 40 × 109/L are below. Data shown as mean ± SD. n = 4, 4, 6 (WBC); n = 5, 4, 6 (RBC). *FDR q < 0.05 (1-way ANOVA). (C) Representative images of blood smear at 7 weeks from recipient mice. Scale bars: 10 μm. (D) Kaplan-Meier tumor-free survival curves of recipient mice (n = 6). **P < 0.01 (log-rank test). (E) The frequencies of mLOY in HSPCs before injection and blast cells in AML mouse tumor cells; tumor cells were harvested from bone marrow at each of the endpoints when recipient mice developed full-blown AML (BM). Data are shown as mean ± SD. n = 3, 2 (preinjection), n = 3, 4 (sgSsty1), n = 3, 4 (sgSsty2). NS, not significant, *P < 0.05, **P < 0.01 (2-way ANOVA). (F) Comet assay of AML tumor cells (3 mice per group). The tail moment is shown as the mean ± SD. ***FDR q < 0.001, ****FDR q < 0.0001 (Kruskal-Wallis test). (G) GSEA showing the enrichment of gene signatures (top 200 differentially expressed genes upregulated or downregulated) of mLOY AML patients and mLOY AML mice compared with WT (mLOY and WT patients were derived from the AML1-ETO samples in the TARGET-AML cohort). (H) GSEA showing the enrichment of the HALLMARK_MYC_TARGET_V2 pathway in both mLOY AML patients and mLOY AML mice compared with WT (mLOY pt, AML patients with mLOY; WT pt, AML patients with intact Y chromosome).