Department of Immunology, Medical University of Warsaw, Nielubowicza 5 St, 02-097 Warsaw, Poland.
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Trojdena 2a St, 02-091 Warsaw, Poland.
Int J Mol Sci. 2020 Aug 12;21(16):5776. doi: 10.3390/ijms21165776.
Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region () gene on chromosome 9 and ABL proto-oncogene 1 () gene on chromosome 22. The fusion gene, , is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.
费城染色体（Ph）是由 9 号染色体上的断裂点簇区（BCR）基因和 22 号染色体上的 ABL 原癌基因（ABL1）基因之间的易位形成的。融合基因 BCR-ABL1 是一种组成性激活的酪氨酸激酶，可促进白血病的发展。根据 基因内的断裂点位置不同，存在不同的 BCR-ABL1 异构体，其中 p210 和 p190 最为常见。p210 异构体是慢性髓系白血病（CML）的标志，而 p190 异构体则在大多数 Ph 阳性 B 细胞急性淋巴细胞白血病（Ph+ B-ALL）病例中表达。CML 和 Ph+ B-ALL 患者治疗方案的关键组成部分是酪氨酸激酶抑制剂（TKI），这些药物针对两种 BCR-ABL1 异构体。虽然 TKI 治疗在大多数 CML 患者中取得了成功，但 Ph+ B-ALL 常常作为耐药性疾病复发。最近，高通量基因组和蛋白质组分析揭示了 CML 和 Ph+ B-ALL 之间存在显著差异。在这篇综述中，我们总结了与不同 BCR-ABL1 异构体介导的信号通路、谱系特异性遗传病变和代谢重编程相关的最新发现。特别是，我们强调了将 Ph+ B-ALL 与 CML 区分开来的特征，并关注利用这些特征的潜在治疗方法，这可能改善 Ph+ B-ALL 的治疗效果。
