PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in human and murine acute myeloid leukemia

被引：21

作者：

Goswami, Swagata ^{[1
,2
]}

Mani, Rajeswaran ^{[3
]}

Nunes, Jessica ^{[1
,2
]}

Chiang, Chi-Ling ^{[1
]}

Zapolnik, Kevan ^{[1
]}

Hu, Eileen ^{[1
]}

Frissora, Frank ^{[1
]}

Mo, Xiaokui ^{[4
]}

Walker, Logan A. ^{[5
]}

Yan, Pearlly ^{[1
,6
]}

Bundschuh, Ralf ^{[6
,7
,8
]}

Beaver, Larry ^{[1
]}

Devine, Raymond ^{[1
]}

Tsai, Yo-Ting ^{[1
]}

Ventura, Ann ^{[1
]}

Xie, Zhiliang ^{[1
]}

Chen, Min ^{[9
]}

Lapalombella, Rosa ^{[1
,6
]}

Walker, Alison ^{[1
,6
]}

Mims, Alice ^{[1
,6
]}

Larkin, Karilyn ^{[1
,6
]}

Grieselhuber, Nicole ^{[1
,6
]}

Bennett, Chad ^{[1
]}

Phelps, Mitch ^{[1
,9
]}

Hertlein, Erin ^{[1
,6
]}

Behbehani, Gregory ^{[1
,6
]}

Vasu, Sumithira ^{[1
,6
]}

Byrd, John C. ^{[1
,6
,9
]}

Muthusamy, Natarajan ^{[1
,6
]}

机构：

[1] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA

[2] Ohio State Univ, Mol Cellular & Dev Biol Grad Program, Columbus, OH 43210 USA

[3] Atrium Hlth, Levine Canc Inst, Charlotte, NC USA

[4] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA

[5] Univ Michigan, Biophys Grad Program, Ann Arbor, MI 48109 USA

[6] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA

[7] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA

[8] Ohio State Univ, Dept Phys, 174 W 18th Ave, Columbus, OH 43210 USA

[9] Ohio State Univ, Coll Pharm, 500 W 12Th Ave, Columbus, OH 43210 USA

来源：

BLOOD | 2022年 / 139卷 / 09期

关键词：

PROTEIN PHOSPHATASE 2A; REGULATORY SUBUNIT B55-ALPHA; TUMOR-SUPPRESSOR PP2A; C-MYC; ACTIVATION; EXPRESSION; FTY720; DIFFERENTIATION; INHIBITION; CANCER;

D O I：

10.1182/blood.2020010344

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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(-/-)Flt3(ITD/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.

引用

页码：1340 / 1358

页数：19

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