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 3

mLOY gives rise to clonal hematopoiesis in mice.

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mLOY gives rise to clonal hematopoiesis in mice. (A) Schematic showing t...
(A) Schematic showing the experimental design. HSPCs from male mCD45.1; Cas9 mice were infected with mCherry-linked Y-chromosome-targeting sgRNA (sgSsty1 and sgSsty2)-sgCas9 and then transplanted into sublethally irradiated (7 Gy) mCD45.2 female recipient mice, with sgScr-sgCas9 as a negative control. (B) RBC counts of recipient mice 9 weeks after transplantation with sgScr-sgCas9, sgSsty1-sgCas9, and sgSsty2-sgCas9 HSPCs. Data shown as mean ± SD (n = 6). *FDR q < 0.05 (1-way ANOVA). (C) Percentages of mLOY in sgScr-sgCas9, sgSsty1-sgCas9, and sgSsty2-sgCas9 HSPCs before injection and donor-derived bone marrow cells at 12 weeks and 21 weeks after transplantation in recipient mice. The gray dotted line shows the growth trend. n = 3, 6 (preinjection), n = 2, 4 (12 weeks), n = 2, 4 (21 weeks). NS, not significant, *P < 0.05, ***P < 0.001 (2-way ANOVA). (D) Representative photomicrographs of FISH of sgScr-sgCas9, sgSsty1-sgCas9, and sgSsty2-sgCas9 HSPCs before injection (top) and bone marrow cells from recipient mice that developed full-blown AML (BM, bottom). Green, FITC-labeled whole-chromosome probe for Y chromosome; red, Texas red–labeled X chromosome probe for XqA7.3; blue, DAPI-labeled DNA. White arrows indicate XO cells. Scale bars: 10 μm.