PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells
PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells
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DOI：
10.1172/jci68951
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发表时间：
2013-10-01
影响因子：
15.9
通讯作者：
Perrotti, Danilo
中科院分区：
文献类型：
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作者：
Neviani, Paolo;Harb, Jason G.;Perrotti, Danilo
酪氨酸激酶抑制剂（TKI）治疗慢性粒细胞白血病（CML）的成功取决于CML祖细胞对BCR-ABL 1激酶活性的需求。然而，CML静止期HSC对TKI具有耐药性，代表了BCR-ABL 1激酶非依赖性疾病储库。在这里，我们已经表明，骨髓中白血病HSC的持续存在需要抑制肿瘤抑制蛋白磷酸酶2A（PP 2A）和BCR-ABL 1癌基因的表达，而不是活性。对CML患者和健康个体的HSC的检查显示，与正常HSC相比，CML中的PP 2A活性受到抑制。TKI耐药CML静止期HSC显示BCR-ABL 1水平升高，但激酶活性非常低。BCR-ABL 1表达，而不是激酶功能，是JAK 2募集、JAK 2/β-连环蛋白存活/自我更新途径激活和PP 2A抑制所必需的。PP 2A激活药物（PAD）通过BCR-ABL 1激酶非依赖性和PP 2A介导的JAK 2和β-连环蛋白抑制，显著降低CML静止期HSC的存活和自我更新，但不影响正常静止期HSC。这导致骨髓异种移植物中人类白血病HSC/祖细胞存活受到抑制，但不正常，并干扰系列移植试验中BCR-ABL 1阳性HSC的长期维持。用PAD靶向静止HSC中的JAK 2/PP 2A/β-连环蛋白网络（例如，FTY 720）具有治疗TKI难治性CML的潜力。减轻患者对TKI的终身依赖。
The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression - but not activity - of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/beta-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and beta-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/beta-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and. relieve lifelong patient dependence on TKIs.