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 1

TET2 mutations are common in TP53-mutant AML and confer an inferior outcome.

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TET2 mutations are common in TP53-mutant AML and confer an inferior out...
(A) Oncoprint of patients with TP53-mutant AML with indication of the top 6 most common co-occurring genetic events as well as cytogenetics and tumor mutational burden (TMB) among 216 patients with AML with somatic TP53 mutations. Data are from Alliance (our unpublished observations), Beat AML (10), and Rodriguez-Meira et al. (11). (B) Density estimation of variant allele frequency (VAF) of TP53 mutations across 668 TP53-mutant patients (subdivided by patients with 1 TP53 mutation, >1 TP53 mutation, or TP53 mutation plus deletion). Data are from AACR Project GENIE (12). (C) As in B but for TET2 mutations from 80 TP53-mutant patients (subdivided by patients with 1 TET2 mutation, >1 TET2 mutation, or TET2 mutation plus deletion). (D) The portion and VAF of TET2 and TP53 mutations in 26 patients with TP53/TET2 comutations. Data are from Alliance, Beat AML (10), and Rodriguez-Meira et al. (11). (E) Kaplan-Meier survival curve in 1,603 patients with AML based on TP53 and TET2 mutational status from Alliance. OS, overall survival. (F) As in E but for an independent cohort of 653 patients with AML from the University of Chicago. A log-rank test was used for survival statistics.