ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia.
ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia.
复制标题
在爆炸危机和抗伊马替尼的慢性骨髓性白血病中重置PP2A肿瘤抑制活性。
DOI：
10.1038/sj.bjc.6603317
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发表时间：
2006-10-09
影响因子：
8.8
通讯作者：
Neviani, P
中科院分区：
文献类型：
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作者：
Perrotti, D;Neviani, P
p210-BCR/ABL癌蛋白激酶活性失调是慢性粒细胞白血病（CML）的标志，诱导并维持白血病表型，并促进疾病进展。甲磺酸伊马替尼是一种BCR/ABL激酶抑制剂，对大多数慢性期CML患者有效。然而，相当比例的CML患者对伊马替尼产生耐药性和/或仍进展至急变，这是一种伊马替尼治疗通常难治的疾病阶段。此外，有令人信服的证据表明CML白血病干细胞也对伊马替尼具有耐药性。因此，仍然需要新的药物，如果与伊马替尼联合使用，将降低复发率，完全克服伊马替尼耐药性，并防止CML的急变。我们最近报道了肿瘤抑制蛋白磷酸酶2A（PP 2A）的活性在急变期CML患者细胞中被显著抑制，并且PP 2A磷酸酶的分子或药理学再活化导致生长抑制，增强凋亡，伊马替尼敏感和耐药的克隆形成能力受损，体内白血病发生减少（包括T315 I）CML-BC患者细胞和/或BCR/ABL+骨髓祖细胞系。因此，PP 2A磷酸酶激活和BCR/ABL激酶抑制药物的组合可能是一个强大的治疗策略，为急变CML患者。
The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL+ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.