TY - JOUR
T1 - PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in human and murine acute myeloid leukemia
AU - Goswami, Swagata
AU - Mani, Rajeswaran
AU - Nunes, Jessica
AU - Chiang, Chi Ling
AU - Zapolnik, Kevan
AU - Hu, Eileen
AU - Frissora, Frank
AU - Mo, Xiaokui
AU - Walker, Logan A.
AU - Yan, Pearlly
AU - Bundschuh, Ralf
AU - Beaver, Larry
AU - Devine, Raymond
AU - Tsai, Yo Ting
AU - Ventura, Ann
AU - Xie, Zhiliang
AU - Chen, Min
AU - Lapalombella, Rosa
AU - Walker, Alison
AU - Mims, Alice
AU - Larkin, Karilyn
AU - Grieselhuber, Nicole
AU - Bennett, Chad
AU - Phelps, Mitch
AU - Hertlein, Erin
AU - Behbehani, Gregory
AU - Vasu, Sumithira
AU - Byrd, John C.
AU - Muthusamy, Natarajan
N1 - Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/3/3
Y1 - 2022/3/3
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2020010344
DO - 10.1182/blood.2020010344
M3 - Article
C2 - 34788382
AN - SCOPUS:85125467362
SN - 0006-4971
VL - 139
SP - 1340
EP - 1358
JO - Blood
JF - Blood
IS - 9
ER -
