| Literature DB >> 34788382 |
Swagata Goswami1,2, Rajeswaran Mani3, Jessica Nunes1,2, Chi-Ling Chiang1, Kevan Zapolnik1, Eileen Hu1, Frank Frissora1, Xiaokui Mo4, Logan A Walker5, Pearlly Yan1,6, Ralf Bundschuh6,7,8, Larry Beaver1, Raymond Devine1, Yo-Ting Tsai1, Ann Ventura1, Zhiliang Xie1, Min Chen9, Rosa Lapalombella1,6, Alison Walker1,6, Alice Mims1,6, Karilyn Larkin1,6, Nicole Grieselhuber1,6, Chad Bennett1, Mitch Phelps1,9, Erin Hertlein1,6, Gregory Behbehani1,6, Sumithira Vasu1,6, John C Byrd1,6,9, Natarajan Muthusamy1,6.
Abstract
Dysregulated cellular differentiation is a hallmark of acute leukemogenesis. Phosphatases are widely suppressed in cancers but have not been traditionally associated with differentiation. In this study, we found that the silencing of protein phosphatase 2A (PP2A) directly blocks differentiation in acute myeloid leukemia (AML). Gene expression and mass cytometric profiling revealed that PP2A activation modulates cell cycle and transcriptional regulators that program terminal myeloid differentiation. Using a novel pharmacological agent, OSU-2S, in parallel with genetic approaches, we discovered that PP2A enforced c-Myc and p21 dependent terminal differentiation, proliferation arrest, and apoptosis in AML. Finally, we demonstrated that PP2A activation decreased leukemia-initiating stem cells, increased leukemic blast maturation, and improved overall survival in murine Tet2-/-Flt3ITD/WT and human cell-line derived xenograft AML models in vivo. Our findings identify the PP2A/c-Myc/p21 axis as a critical regulator of the differentiation/proliferation switch in AML that can be therapeutically targeted in malignancies with dysregulated maturation fate.Entities:
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Year: 2022 PMID： 34788382 PMCID： PMC8900275 DOI： 10.1182/blood.2020010344
Source DB: PubMed Journal: Blood ISSN： 0006-4971 Impact factor: 25.476