Tumor suppressor function of Gata2 in acute promyelocytic leukemia

Casey D.S. Katerndahl, Olivia R.S. Rogers, Ryan B. Day, Michelle A. Cai, Timothy P. Rooney, Nichole M. Helton, Mieke Hoock, Sai Mukund Ramakrishnan, Sridhar Nonavinkere Srivatsan, Lukas D. Wartman, Christopher A. Miller, Timothy J. Ley

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Most patients with acute promyelocytic leukemia (APL) can be cured with combined all-trans retinoic acid (ATRA) and arsenic trioxide therapy, which induces the destruction of PML-RARA, the initiating fusion protein for this disease. However, the underlying mechanisms by which PML-RARA initiates and maintains APL cells are still not clear. Therefore, we identified genes that are dysregulated by PML-RARA in mouse and human APL cells and prioritized GATA2 for functional studies because it is highly expressed in preleukemic cells expressing PML-RARA, its high expression persists in transformed APL cells, and spontaneous somatic mutations of GATA2 occur during APL progression in mice and humans. These and other findings suggested that GATA2 may be upregulated to thwart the proliferative signal generated by PML-RARA and that its inactivation by mutation (and/or epigenetic silencing) may accelerate disease progression in APL and other forms of acute myeloid leukemia (AML). Indeed, biallelic knockout of Gata2 with CRISPR/Cas9-mediated gene editing increased the serial replating efficiency of PML-RARA–expressing myeloid progenitors (as well as progenitors expressing RUNX1-RUNX1T1, or deficient for Cebpa), increased mouse APL penetrance, and decreased latency. Restoration of Gata2 expression suppressed PML-RARA–driven aberrant self-renewal and leukemogenesis. Conversely, addback of a mutant GATA2R362G protein associated with APL and AML minimally suppressed PML-RARA–induced aberrant self-renewal, suggesting that it is a loss-of-function mutation. These studies reveal a potential role for Gata2 as a tumor suppressor in AML and suggest that restoration of its function (when inactivated) may provide benefit for AML patients.

Original languageEnglish
Pages (from-to)1148-1161
Number of pages14
JournalBlood
Volume138
Issue number13
DOIs
StatePublished - Sep 30 2021

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