Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists
Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists
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DOI：
10.1038/nature15248
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发表时间：
2015-09-17
期刊：
影响因子：
64.8
通讯作者：
Leboulch, Philippe
中科院分区：
文献类型：
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作者：
Prost, Stephane;Relouzat, Francis;Leboulch, Philippe
癌症是由少量干细胞维持还是由具有近似表型等效性的增殖细胞组成是癌症生物学的核心问题(1)。在干细胞假说中，治疗后的复发可能是由于未能根除癌症干细胞而发生的。慢性粒细胞白血病（CML）是这一假设的典型。 CML 是一种骨髓增生性疾病，由融合癌蛋白 BCR-ABL(2) 的酪氨酸激酶活性失调引起。在慢性期，干细胞水平上的这种唯一遗传异常（染色体易位 Ph+：t(9;22)(q34;q11)）会导致骨髓细胞增殖增加，但不会丧失其分化能力。如果不进行治疗，大多数患者会进入急变期，此时额外的致癌突变会导致由增殖的未成熟细胞组成的致命性急性白血病。甲磺酸伊马替尼和其他针对 BCR-ABL 激酶活性的酪氨酸激酶抑制剂 (TKI) 显着提高了患者的生存率。然而，只有不到 10% 的患者达到完全分子缓解 (CMR) 阶段，即血细胞中无法检测到 BCR-ABL 转录本的阶段 (3)。未能达到 CMR 的原因是 TKI 无法根除静态 CML 白血病干细胞 (LSC)(2-4)。在这里，我们表明，残留的 CML LSC 库可以通过格列酮（一种抗糖尿病药物，过氧化物酶体增殖物激活受体-γ（PPAR γ）的激动剂）逐渐清除。我们发现格列酮激活 PPAR γ 会降低 STAT5 及其下游靶标 HIF2 α(5) 和 CITED2(6) 的表达，这些靶标是 CML LSC 静止和干性的关键守护者。当三名患有慢性残留病的 CML 患者在持续接受伊马替尼治疗的情况下暂时给予吡格列酮时，他们都实现了持续的 CMR，在吡格列酮停药后长达 4.7 年。这表明临床相关的癌症根除可能成为通过侵蚀癌症干细胞库的联合疗法普遍实现的目标。
Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology(1). In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL(2). During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph+: t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells(3). Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs)(2-4). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-gamma (PPAR gamma). We found that activation of PPAR gamma by the glitazones decreases expression of STAT5 and its downstreamtargets HIF2 alpha(5) and CITED2(6), which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.