Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities
Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (<i>BCR</i>) gene on chromosome 9 and ABL proto-oncogene 1 (<i>ABL1</i>) gene on chromosome 22. The fusion gene, <i>BCR-ABL1</i>, is a constitutively active tyrosine ki...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/16/5776 |
| Summary: | Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (<i>BCR</i>) gene on chromosome 9 and ABL proto-oncogene 1 (<i>ABL1</i>) gene on chromosome 22. The fusion gene, <i>BCR-ABL1</i>, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the <i>BCR</i> 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. |
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| ISSN: | 1661-6596 1422-0067 |