TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment
Pu Zhang, et al.
Pu Zhang, et al.
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Research Article Hematology Inflammation Oncology

TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment

Abstract

Mutations and deletions in TP53 are associated with adverse outcomes in patients with myeloid malignancies, and there is an urgent need for the development of improved therapies for TP53-mutant leukemias. Here, we identified mutations in TET2 as the most common co-occurring mutation in patients with TP53-mutant acute myeloid leukemia (AML). In mice, combined hematopoietic-specific deletion of TET2 and TP53 resulted in enhanced self-renewal compared with deletion of either gene alone. Tp53/Tet2 double-KO mice developed serially transplantable AML. Both mice and patients with AML with combined TET2/TP53 alterations upregulated innate immune signaling in malignant granulocyte-monocyte progenitors, which had leukemia-initiating capacity. A20 governs the leukemic maintenance by triggering aberrant noncanonical NF-κB signaling. Mice with Tp53/Tet2 loss had expansion of monocytic myeloid-derived suppressor cells (MDSCs), which impaired T cell proliferation and activation. Moreover, mice and patients with AML with combined TP53/TET2 alterations displayed increased expression of the TIGIT ligand, CD155, on malignant cells. TIGIT-blocking antibodies augmented NK cell–mediated killing of Tp53/Tet2 double-mutant AML cells, reduced leukemic burden, and prolonged survival in Tp53/Tet2 double-KO mice. These findings describe a leukemia-promoting link between TET2 and TP53 mutations and highlight therapeutic strategies to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML.

Authors

Pu Zhang, Ethan C. Whipp, Sarah J. Skuli, Mehdi Gharghabi, Caner Saygin, Steven A. Sher, Martin Carroll, Xiangyu Pan, Eric D. Eisenmann, Tzung-Huei Lai, Bonnie K. Harrington, Wing Keung Chan, Youssef Youssef, Bingyi Chen, Alex Penson, Alexander M. Lewis, Cynthia R. Castro, Nina Fox, Ali Cihan, Jean-Benoit Le Luduec, Susan DeWolf, Tierney Kauffman, Alice S. Mims, Daniel Canfield, Hannah Phillips, Katie E. Williams, Jami Shaffer, Arletta Lozanski, Tzyy-Jye Doong, Gerard Lozanski, Charlene Mao, Christopher J. Walker, James S. Blachly, Anthony F. Daniyan, Lapo Alinari, Robert A. Baiocchi, Yiping Yang, Nicole R. Grieselhuber, Moray J. Campbell, Sharyn D. Baker, Bradley W. Blaser, Omar Abdel-Wahab, Rosa Lapalombella

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Figure 5

Myeloid predisposition and enhanced innate immune signaling in Tp53–/–Tet2–/– precursor cells.

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Myeloid predisposition and enhanced innate immune signaling in Tp53–/–Te...
(A) Heatmap of top differentially expressed genes (FDR < 0.05) within the myeloid differentiation pathway of LSK cells from 4-month-old mice with different genotypes. Key myeloid transcriptional factors upregulated in Tp53/Tet2 double-KO LSK cells relative to other groups are highlighted. (B) GSEA plots of inflammatory responses and the Myc pathway in LSK cells from Tp53–/–Tet2–/– mice with AML relative to control mice. (C) Western blot of TLR2, A20, noncanonical NF-κB pathway components (NIK, p52/p100, and phosphorylated p100 [p-p100] in whole-cell lysate [WCL] and RelB in nuclear extract [NE]) and canonical NF-κB pathway members (p65, phosphorylated-IKKα [p-IKKα], and IKKα) in cKit+ bone marrow cells from age-matched mice with indicated genotypes (3 mice per group). β-Actin and Lamin B1 served as housekeeping controls in WCL and NE, respectively. (D) Western blot of TLR2, A20, NIK, and p52/p100 in WCL and RelB in NE from patients with combined TET2 and TP53 mutations, either mutation alone, or neither TET2 or TP53 mutations (WT). β-Actin and Lamin B1 served as housekeeping controls in WCL and NE, respectively. Analysis of fold change normalized to the control lane is shown below immunoblot where indicated. (E) Western blot of A20, phosphorylated IkBα (p-IkBα), and total IkBα in WCL and RelB and RelA in NE in cKit+ bone marrow cells of Tp53–/–Tet2–/– mice treated with control (sgNeg) or 1 of 2 A20-targeting sgRNAs. β-Actin and Lamin B1 served as housekeeping controls in WCL and NE, respectively. (F) Mean number of methylcellulose colonies in cells from E and WT bone marrow cells treated with control or 1 of 2 A20-targeting sgRNAs. Mean ± SD shown. **P < 0.01. Results are representative of 2–3 independent experiments. Tp53–/–Tet2–/–, Vav-cre Tet2fl/fl Tp53fl/fl; Tet2–/–, Vav-cre Tet2fl/fl; Tp53–/–, Vav-cre Tp53fl/fl; WT, Vav-cre.