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Ezh2 loss propagates hypermethylation at T cell differentiation–regulating genes to promote leukemic transformation
Changshan Wang, … , Atsushi Iwama, Goro Sashida
Changshan Wang, … , Atsushi Iwama, Goro Sashida
Published August 6, 2018
Citation Information: J Clin Invest. 2018;128(9):3872-3886. https://doi.org/10.1172/JCI94645.
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Research Article Hematology Oncology

Ezh2 loss propagates hypermethylation at T cell differentiation–regulating genes to promote leukemic transformation

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Abstract

Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a new pathological entity with poor outcomes in T cell ALL (T-ALL) that is characterized by a high incidence of loss-of-function mutations in polycomb repressive complex 2 (PRC2) genes. We generated a mouse model of ETP-ALL by deleting Ezh2, one of the PRC2 genes, in p53-null hematopoietic cells. The loss of Ezh2 in p53-null hematopoietic cells impeded the differentiation of ETPs and eventually induced ETP-ALL–like disease in mice, indicating that PRC2 functions as a bona fide tumor suppressor in ETPs. A large portion of PRC2 target genes acquired DNA hypermethylation of their promoters following reductions in H3K27me3 levels upon the loss of Ezh2, which included pivotal T cell differentiation–regulating genes. The reactivation of a set of regulators by a DNA-demethylating agent, but not the transduction of single regulator genes, effectively induced the differentiation of ETP-ALL cells. Thus, PRC2 protects key T cell developmental regulators from DNA hypermethylation in order to keep them primed for activation upon subsequent differentiation phases, while its insufficiency predisposes ETPs to leukemic transformation. These results revealed a previously unrecognized epigenetic switch in response to PRC2 dysfunction and provide the basis for specific rational epigenetic therapy for ETP-ALL with PRC2 insufficiency.

Authors

Changshan Wang, Motohiko Oshima, Daisuke Sato, Hirotaka Matsui, Sho Kubota, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Shuhei Koide, Jun Matsubayashi, Makiko Mochizuki-Kashio, Takako Nakano-Yokomizo, Jie Bai, Toshitaka Nagao, Akinori Kanai, Atsushi Iwama, Goro Sashida

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Figure 1

Ezh2 loss impaired hematopoiesis and caused lethal disease in the absence of p53.

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Ezh2 loss impaired hematopoiesis and caused lethal disease in the absenc...
(A) Experimental schematic of our mouse model utilizing Ezh2 and/or p53 conditional knockout BM cells transplanted into lethally irradiated WT CD45.1+ recipients. (B) Quantitative RT-PCR analysis of the expression of Ezh2 and p53 in CD44+CD25–CD4–CD8– (DN1) cells from WT (n = 4) and Ezh2Δ/Δp53Δ/Δ mice (n = 4) 4 weeks after the deletion of Ezh2 and p53. Gapdh was used to normalize the amount of input RNA. Data are shown as mean ± SD. *P < 0.05, Mann-Whitney U test. N.D., not determined. (C) Verification of H3K27me3 levels in CD4–CD8– (DN) cells from WT, Ezh2Δ/Δ, p53Δ/Δ, and Ezh2Δ/Δp53Δ/Δ mice examined by Western blotting. Histone H3 was used as a loading control. (D) Complete blood cell counts of WT (n = 10), Ezh2Δ/Δ (n = 13), p53Δ/Δ (n = 15), and Ezh2Δ/Δp53Δ/Δ (n = 14) mice 3 months after transplantation and moribund Ezh2Δ/Δp53Δ/Δ ETP-ALL mice (n = 11) at the time of sacrifice. Data are shown as box-and-whiskers plots drawing minimum to maximum. *P < 0.05; **P < 0.01; ***P < 0.001, Student’s t test. (E) Proportions of myeloid (Gr-1+ and/or Mac-1+), B220+ B cells, CD4+ or CD8+ T cells, and immature cells negative for these surface markers among CD45.2+ donor-derived hematopoietic cells in PB. Data are shown as mean ± SEM (n = 10–15). (F) Thymus weight of WT mice (n = 10) 3 months after transplantation and p53Δ/Δ T-ALL mice (n = 9) at the time of sacrifice. Data are shown as mean ± SEM. ***P < 0.001, Mann-Whitney U test. (G) Histology of the thymus of a p53Δ/Δ T-ALL mouse observed by H&E staining (top) and CD3 staining (bottom). Original magnification, ×400. Scale bars: 20 μm. (H) Representative flow cytometric profiles of CD45+-gated thymocytes in the thymus of a p53Δ/Δ T-ALL mouse shown from F (n = 9). (I) Kaplan-Meier survival curve. Median survival was significantly shorter in Ezh2Δ/Δp53Δ/Δ mice (n = 14) than in Ezh2Δ/Δ mice (n = 13) (189 days versus 327.5 days), but longer in Ezh2Δ/Δp53Δ/Δ mice (n = 14) than in p53Δ/Δ mice (n = 15) (189 days versus 137 days). ***P < 0.0001, log-rank test.
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