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.

中文翻译：

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PP2A 是人类和小鼠急性髓系白血病中通过 c-Myc/p21 轴决定细胞命运的治疗靶向驱动因素。

细胞分化失调是急性白血病发生的标志。磷酸酶在癌症中被广泛抑制，但传统上与分化无关。在这项研究中，我们发现蛋白磷酸酶 2A (PP2A) 的沉默直接阻断急性髓系白血病 (AML) 的分化。基因表达和质谱流式分析表明，PP2A 激活可调节细胞周期和转录调节因子，从而编程终末骨髓分化。使用新型药物 OSU-2S 与遗传方法并行，我们发现 PP2A 在 AML 中强制 c-Myc 和 p21 依赖性终末分化、增殖停滞和细胞凋亡。最后，我们证明，在小鼠 Tet2-/-Flt3ITD/WT 和人细胞系衍生的异种移植 AML 模型中，PP2A 激活可减少白血病起始干细胞，增加白血病原始细胞成熟，并提高总体存活率。我们的研究结果确定 PP2A/c-Myc/p21 轴是 AML 分化/增殖转换的关键调节因子，可作为成熟命运失调的恶性肿瘤的治疗靶点。