慢性髓系白血病急变期分子遗传学研究进展

9号和22号染色体相互易位产生Ph染色体及BCR-ABL融合基因,几乎在所有慢性髓系白血病（CML）出现,BCR-ABL编码的蛋白具有持续增高的酪氨酸激酶活性,使白血病细胞异常增殖。急变期是CML的晚期,在此期间常常出现其它附加染色体和分子的改变。大量研究表明,BCR-ABL基因与其他失调的基因共同作用并异常激活下游的信号传导通路,促进了疾病的进展。酪氨酸激酶抑制剂伊马替尼对大多数慢性期CML患者治疗效果显著。IRIS5年的临床试验显示：用伊马替尼治疗的98%患者达血液学完全缓解,92%患者达主要细胞遗传学缓解,87%患者达完全细胞遗传学缓解。然而,仍有少数慢性期和大多数进展期患者用伊马替尼治疗疗效欠佳。在耐药机制的研究中发现ABL激酶区点突变与临床耐药关系密切。第二代酪氨酸激酶抑制剂可改善伊马替尼耐药,本文就急性变的分子机制、伊马替尼耐药等做一综述。

Research Advance On Molecular Genetics of CML Blast Crisis-Review

Philadelphia (Ph) chromosome at (9; 22) reciprocal chromosomal translocation producing BCR-ABL fusion gene, emerges in almost all patients with chronic myeloid leukemia (CML). The protein product of BCR-ABL is a constitutively active tyrosine kinase that drives the abnormal proliferation of CML cells. Blast crisis (BC) is the terminal phase of CML, which is often associated with additional chromosomal and molecular secondary changes. Although the mechanisms responsible for transition of CML chronic phase (CP) into BC remain poorly understood, ample evidence suggests that it depends on synergy of BCR/ABL with other genes dysregulated during disease progression, and signaling pathways are abnormally activated by BCR/ABL. With the application of imatinib, a ABL-specific tyrosine kinase inhibitor, its remarkable therapeutic effects suggest that blast crisis transition will be postponed in most patients with CML. Rate of cumulative best response in CML-CP patients from the IRIS trial after 5 years are 98% for complete hematologic response, 92% for major cytogenetic response and 87% for complete cytogenetic response. However, a minority of CML-CP patients and most patients in progression either fail or respond suboptimally to imatinib. There are many distinct patterns of resistance, and ABL kinase mutations is a common finding associated with clinical resistance. Dasatinib and nilotinib can restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase. This review illustrates the molecular mechanisms underlying transition to CML-BC, also addresses oneself to how and why imatinib resistance occurs.