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

Pu Zhang,¹ Ethan C. Whipp,¹ Sarah J. Skuli,² Mehdi Gharghabi,¹ Caner Saygin,³ Steven A. Sher,¹ Martin Carroll,² Xiangyu Pan,⁴ Eric D. Eisenmann,⁵ Tzung-Huei Lai,¹ Bonnie K. Harrington,⁶ Wing Keung Chan,¹ Youssef Youssef,¹ Bingyi Chen,⁷ Alex Penson,⁷ Alexander M. Lewis,⁷ Cynthia R. Castro,⁷ Nina Fox,⁷ Ali Cihan,⁸ Jean-Benoit Le Luduec,⁷ Susan DeWolf,⁷ Tierney Kauffman,¹ Alice S. Mims,¹ Daniel Canfield,¹ Hannah Phillips,¹ Katie E. Williams,¹ Jami Shaffer,¹ Arletta Lozanski,¹ Tzyy-Jye Doong,¹ Gerard Lozanski,¹ Charlene Mao,¹ Christopher J. Walker,¹ James S. Blachly,¹ Anthony F. Daniyan,⁸ Lapo Alinari,¹ Robert A. Baiocchi,¹ Yiping Yang,¹ Nicole R. Grieselhuber,¹ Moray J. Campbell,⁹ Sharyn D. Baker,⁵ Bradley W. Blaser,¹ Omar Abdel-Wahab,⁷ and Rosa Lapalombella¹

Published March 20, 2025 - More info

Mutations and deletions in TP53 are associated with adverse outcomes in patients with myeloid malignancies and developing improved therapies for TP53-mutant leukemias is of urgent need. Here we identify mutations in TET2 as the most common co-occurring mutation in TP53 mutant acute myeloid leukemia (AML) patients. In mice, combined hematopoietic-specific deletion of TET2 and TP53 resulted in enhanced self-renewal compared to deletion of either gene alone. Tp53/Tet2 double knockout mice developed serially transplantable AML. Both mice and AML patients with combined TET2/TP53 alterations upregulated innate immune signaling in malignant granulocyte-monocyte progenitors (GMPs), which had leukemia-initiating capacity. A20 governs the leukemic maintenance by triggering aberrant non-canonical 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 AML patients 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 knockout mice. These findings uncover 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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