Abstract
Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR 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.
Highlights
BCR-ABL1 is a constitutively active tyrosine kinase encoded by the fusion gene consisting of the breakpoint cluster region (BCR) and the ABL proto-oncogene 1 (ABL1)
Mediated in the lightbyofthe recent we discuss novel, targeted, lymphoid overview of recently published research on lineage-specific differences in crucial signaling pathways lineage-specific treatment options, both already tested in clinical trials and those that have shown other than BCR-ABL1
chronic myeloid leukemia (CML) is usually diagnosed in a manageable, chronic phase (CP), but it can progress into accelerated phase (AP) or a fatal blast phase (BP)
Summary
BCR-ABL1 is a constitutively active tyrosine kinase encoded by the fusion gene consisting of the breakpoint cluster region (BCR) and the ABL proto-oncogene 1 (ABL1). BCR-ABL1 in leukemic cells is sufficient to initiate and promote diseases are different in terms of molecular and clinical features. Introduction of or TKIs to CML treatment protocols was a major advanced, blast phase of myeloid lymphoid origin. Research of the last ABL1-derived decade uncovers a plethora of (KD), linage-specific mutations andsignificant signaling differences in the interactomes, signaling, and the subcellular localization of the two isoforms [6,12]. TKIs. Wepathways highlight overview of recently published on lineage-specific in crucial majorthan differences in signaling twofindings, main BCR-ABL1 isoforms. Mediated in the lightbyofthe recent we discuss novel, targeted, lymphoid overview of recently published research on lineage-specific differences in crucial signaling pathways lineage-specific treatment options, both already tested in clinical trials and those that have shown other than BCR-ABL1.
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