TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment Journal Article
| Authors: | Zhang, P.; Whipp, E. C.; Skuli, S. J.; Gharghabi, M.; Saygin, C.; Sher, S. A.; Carroll, M.; Pan, X.; Eisenmann, E. D.; Lai, T. H.; Harrington, B. K.; Chan, W. K.; Youssef, Y.; Chen, B.; Penson, A.; Lewis, A. M.; Castro, C. R.; Fox, N.; Cihan, A.; Le Luduec, J. B.; DeWolf, S.; Kauffman, T.; Mims, A. S.; Canfield, D.; Phillips, H.; Williams, K. E.; Shaffer, J.; Lozanski, A.; Doong, T. J.; Lozanski, G.; Mao, C.; Walker, C. J.; Blachly, J. S.; Daniyan, A. F.; Alinari, L.; Baiocchi, R. A.; Yang, Y.; Grieselhuber, N. R.; Campbell, M. J.; Baker, S. D.; Blaser, B. W.; Abdel-Wahab, O.; Lapalombella, R. |
| Article Title: | 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. © 2025, Zhang et al. |
| Keywords: | dna binding protein; tet2 protein, human; genetics; mutation; dna-binding proteins; leukemia, myeloid, acute; proto-oncogene proteins; mouse; animal; animals; mice; mice, knockout; pathology; protein p53; immunology; tumor suppressor protein p53; natural killer cell; killer cells, natural; tp53 protein, human; knockout mouse; acute myeloid leukemia; dioxygenase; humans; human; female; myeloid-derived suppressor cells; myeloid-derived suppressor cell; proto oncogene protein; dioxygenases; trp53 protein, mouse; tet2 protein, mouse |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 135 |
| Issue: | 10 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2025-05-15 |
| Start Page: | e184021 |
| Language: | English |
| DOI: | 10.1172/jci184021 |
| PUBMED: | 40111422 |
| PROVIDER: | scopus |
| PMCID: | PMC12077897 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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