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

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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-03-20
DOI
https://doi.org/10.1172/jci184021
Citations
5
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
8.85

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article

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

Nicole R. Grieselhuber, Nina Fox, Tzyy-Jye Doong, Bradley W. Blaser et al.
5 citations
Journal of Clinical Investigation
Acute Myeloid Leukemia Research
8.85
article

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

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

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.

Journal of Clinical InvestigationVol. 135(10)
Cedars-Sinai Medical Center (US), Memorial Sloan Kettering Cancer Center (US), Cornell University (US), The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US), Kettering University (US), University of Chicago (US), Weill Cornell Medicine (US), The Ohio State University (US), University of Pennsylvania (US), Michigan State University (US)
Damon Runyon Cancer Research Foundation, Leukemia and Lymphoma Society, Edward P. Evans Foundation, NHLBI Division of Intramural Research
Openalex Percentile: Top 2%
Acute Myeloid Leukemia Research
8.85
DOIOpen Access PDFOpenAlex
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