Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells.
Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells.
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DOI：
10.1038/nature18288
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发表时间：
2016-06-16
期刊：
影响因子：
64.8
通讯作者：
Holyoake TL
中科院分区：
文献类型：
--
作者：
Abraham SA;Hopcroft LE;Carrick E;Drotar ME;Dunn K;Williamson AJ;Korfi K;Baquero P;Park LE;Scott MT;Pellicano F;Pierce A;Copland M;Nourse C;Grimmond SM;Vetrie D;Whetton AD;Holyoake TL
慢性粒细胞白血病(CML)是由蛋白酪氨酸激酶BCR-ABL1转化的造血干细胞引起的。直接抑制BCR-ABL1激酶使疾病管理发生了革命性变化，但未能根除维持慢性粒细胞白血病的白血病干细胞(LSC)。LSC的存活不依赖于BCR-ABL1，这为识别和靶向激酶非依赖性通路提供了理论基础。在这里，我们使用蛋白质组学、转录组学和网络分析表明，在人类LSC异常表达的蛋白质中，伊马替尼应答和无应答的患者都受到p53和c-Myc调控的调节。P53和c-Myc的干扰，而不是bcr-abl1本身的干扰，导致在小鼠体内协同杀伤、分化和几乎消除可移植的人LSC，同时保留正常的HSC。这种以连接节点为目标的无偏见的系统方法例证了一种新的精准医学战略，提供了可以根除LSC的证据。
Chronic myeloid leukaemia (CML) arises following transformation of a haemopoietic stem cell (HSC) by protein-tyrosine kinase BCR-ABL1. Direct inhibition of BCR-ABL1 kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSC), which maintain CML. LSC are independent of BCR-ABL1 for survival, providing a rationale to identify and target kinase-independent pathways. Here we show using proteomics, transcriptomics and network analyses, that in human LSC aberrantly expressed proteins, in both imatinib-responder and non-responder patients are modulated in concert with p53 and c-Myc regulation. Perturbation of both p53 and c-Myc, not BCR-ABL1 itself, leads to synergistic kill, differentiation and near elimination of transplantable human LSC in mice, whilst sparing normal HSC. This unbiased systems approach targeting connected nodes exemplifies a novel precision medicine strategy providing evidence that LSC can be eradicated.