PDF(Pubmed)
Abstract：
Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR-ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR-ABL1-transformed mouse pre-B cells, as the deletion of CXCR4 induces death in these cells. To investigate whether CXCR4 inhibition also effectively blocks BCR-ABL1-transformed cell growth in vitro, in this study, we explored an array of peptide-based inhibitors of CXCR4. The inhibitors were optimized derivatives of EPI-X4, an endogenous peptide antagonist of CXCR4. We observed that among all the candidates, EPI-X4 JM#170 (referred to as JM#170) effectively induced cell death in BCR-ABL1-transformed mouse B cells but had little effect on untransformed wild-type B cells. Importantly, AMD3100, a small molecule inhibitor of CXCR4, did not show this effect. Treatment with JM#170 induced transient JNK phosphorylation in BCR-ABL1-transformed cells, which in turn activated the intrinsic apoptotic pathway by inducing cJun, Bim, and Bax gene expressions. Combinatorial treatment of JM#170 with ABL1 kinase inhibitor Imatinib exerted a stronger killing effect on BCR-ABL1-transformed cells even at a lower dose of Imatinib. Surprisingly, JM#170 actively killed Sup-B15 cells, a BCR-ABL1+ human ALL cell line, but had no effect on the BCR-ABL1- 697 cell line. This suggests that the inhibitory effect of JM#170 is specific for BCR-ABL1+ ALL. Taken together, JM#170 emerges as a potent novel drug against Ph+ ALL.
摘要：
费城染色体阳性急性淋巴细胞白血病（PhALL）的特征是9号和22号染色体之间的相互染色体易位，导致组成型活性致癌BCR-ABL1融合蛋白的表达。CXC趋化因子受体4（CXCR4）对于BCR-ABL1转化的小鼠前B细胞的存活至关重要，因为CXCR4的缺失在这些细胞中诱导死亡。为了研究CXCR4抑制是否也在体外有效阻断BCR-ABL1转化的细胞生长，在这项研究中，我们探索了一系列基于肽的CXCR4抑制剂。抑制剂是EPI-X4的优化衍生物，EPI-X4是CXCR4的内源性肽拮抗剂。我们观察到，在所有候选人中，EPI-X4JM#170(称为JM#170)在BCR-ABL1转化的小鼠B细胞中有效诱导细胞死亡,但对未转化的野生型B细胞影响很小。重要的是,CXCR4的小分子抑制剂AMD3100没有显示这种作用。用JM#170处理诱导BCR-ABL1转化细胞中的瞬时JNK磷酸化,通过诱导cJun激活内在的凋亡途径，Bim,和Bax基因表达。用ABL1激酶抑制剂伊马替尼组合处理JM#170对BCR-ABL1转化的细胞发挥更强的杀伤作用,即使在较低剂量的伊马替尼。令人惊讶的是,JM#170主动杀死Sup-B15细胞,BCR-ABL1+人ALL细胞系，但对BCR-ABL1-697细胞系没有影响。这表明JM#170的抑制作用对BCR-ABL1+ALL是特异性的。一起来看,JM#170作为抗Ph+ALL的有效新药出现。
