TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment
Pu Zhang, … , Omar Abdel-Wahab, Rosa Lapalombella
Pu Zhang, … , Omar Abdel-Wahab, Rosa Lapalombella
Published March 20, 2025
Citation Information: J Clin Invest. 2025;135(10):e184021. https://doi.org/10.1172/JCI184021.
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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 4

Increased hematopoietic progenitor self-renewal in Tp53/Tet2 double-KO mice.

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Increased hematopoietic progenitor self-renewal in Tp53/Tet2 double-KO m...
(A) Number of colonies from plating of 10,000 cells from the bone marrow of 16-week-old Vav-cre Tp53fl/flTet2fl/fl mice and controls in methylcellulose. Mean ± SD of 3 technical replicates. (B) Kaplan-Meier curves of recipient CD45.1+ mice following competitive transplantation of bone marrow cells (1 × 106 cells) from leukemic CD45.2+ primary transgenic mice with the indicated genotypes into lethally irradiated recipient mice with CD45.1+ supporting bone marrow cells (1 × 106 cells). n = 10 WT mice, n = 10 Tp53–/– mice, n = 12 Tet2–/– mice, and n = 10 Tp53–/–Tet2–/– mice. (C) Box-and-whisker plots of CD45.2+ cells in peripheral blood of mice from B. Boxes represent median, first, and third quartiles, with whiskers extending to 1.5× interquartile range. n = 10 mice/genotype. (D) Disease incidence in moribund recipient mice following competitive transplantation of bone marrow cells from primary transgenic mice with the indicated genotypes. T-ALL, T acute lymphoblastic leukemia; CMML, chronic myelomonocytic leukemia; AML, acute myeloid leukemia. Tp53–/–Tet2–/–, Vav-cre Tet2fl/fl Tp53fl/fl; Tet2–/–, Vav-cre Tet2fl/fl; Tp53–/–, Vav-cre Tp53fl/fl; WT, Vav-cre. A log-rank test was used for survival statistics; otherwise, ANOVA with Dunnett’s test was used for P values. *P < 0.05; **P < 0.01; ***P < 0.001.