Potent antiproliferative effect of fatty‐acid derivative AIC‐47 on leukemic mice harboring BCR‐ABL mutation
Potent antiproliferative effect of fatty‐acid derivative AIC‐47 on leukemic mice harboring BCR‐ABL mutation
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DOI：
10.1111/cas.13913
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发表时间：
2019-01
期刊：
影响因子：
5.7
通讯作者：
Haruka Shinohara;N. Sugito;Yuki Kuranaga;K. Heishima;Y. Minami;T. Naoe;Y. Akao
中科院分区：
文献类型：
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作者：
Haruka Shinohara;N. Sugito;Yuki Kuranaga;K. Heishima;Y. Minami;T. Naoe;Y. Akao
基于靶向抑制BCR-ABL酪氨酸激酶的治疗大大改善了费城染色体（Ph）阳性白血病患者的预后，酪氨酸激酶抑制剂（TKI）已成为标准治疗。然而，一些患者获得了对TKI的耐药，这通常与BCR-ABL的点突变相关。我们先前报道了中链脂肪酸衍生物AIC-47诱导BCR-ABL的转录抑制和瓦尔堡效应的扰动，导致Ph阳性白血病细胞的生长抑制。在此，我们表明AIC-47在野生型（WT）或突变的BCR-ABL-携带细胞中具有抗白血病作用。AIC-47通过下调转录激活因子c-Myc抑制BCR-ABL基因的转录，而不管突变如何。据报道，代谢途径的重编程与抗癌药物的耐药性有关;然而，我们发现BCR‐ABL的点突变与丙酮酸激酶肌（PKM）亚型表达谱无关。即使在T315 I突变的细胞中，AIC-47也诱导PKM亚型的表达谱从PKM 2转换为PKM 1，这表明AIC-47破坏了瓦尔堡效应。在白血病小鼠模型中，AIC-47极大地抑制了BCR-ABL mRNA水平的增加，并改善了肝脾肿大，无论BCR-ABL突变如何。值得注意的是，AIC-47对脾肿大的改善是显著的，可能等于或大于TKI。这些发现表明，AIC-47可能是克服Ph阳性白血病对治疗的耐药性的有前途的药物。
Therapy based on targeted inhibition of BCR‐ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)‐positive leukemia and tyrosine kinase inhibitors (TKI) have become standard therapy. However, some patients acquire resistance to TKI that is frequently associated with point mutations in BCR‐ABL. We previously reported that a medium‐chain fatty‐acid derivative AIC‐47 induced transcriptional suppression of BCR‐ABL and perturbation of the Warburg effect, leading to growth inhibition in Ph‐positive leukemia cells. Herein, we showed that AIC‐47 had anti‐leukemic effects in either wild type (WT)‐ or mutated‐BCR‐ABL‐harboring cells. AIC‐47 suppressed transcription of BCR‐ABL gene regardless of the mutation through downregulation of transcriptional activator, c‐Myc. Reprogramming of the metabolic pathway has been reported to be associated with resistance to anti‐cancer drugs; however, we found that a point mutation of BCR‐ABL was independent of the profile of pyruvate kinase muscle (PKM) isoform expression. Even in T315I‐mutated cells, AIC‐47 induced switching of the expression profile of PKM isoforms from PKM2 to PKM1, suggesting that AIC‐47 disrupted the Warburg effect. In a leukemic mouse model, AIC‐47 greatly suppressed the increase in BCR‐ABL mRNA level and improved hepatosplenomegaly regardless of the BCR‐ABL mutation. Notably, the improvement of splenomegaly by AIC‐47 was remarkable and might be equal to or greater than that of TKI. These findings suggest that AIC‐47 might be a promising agent for overcoming the resistance of Ph‐positive leukemia to therapy.