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: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/16/5776 |
| _version_ | 1797558697545695232 |
|---|---|
| author | Lukasz Komorowski Klaudyna Fidyt Elżbieta Patkowska Malgorzata Firczuk |
| author_facet | Lukasz Komorowski Klaudyna Fidyt Elżbieta Patkowska Malgorzata Firczuk |
| author_sort | Lukasz Komorowski |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:35:07Z |
| format | Article |
| id | doaj.art-0166d50841414606a774dcf7cfb22edc |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T17:35:07Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0166d50841414606a774dcf7cfb22edc2023-11-20T09:52:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012116577610.3390/ijms21165776Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific VulnerabilitiesLukasz Komorowski0Klaudyna Fidyt1Elżbieta Patkowska2Malgorzata Firczuk3Department of Immunology, Medical University of Warsaw, Nielubowicza 5 St, 02-097 Warsaw, PolandDepartment of Immunology, Medical University of Warsaw, Nielubowicza 5 St, 02-097 Warsaw, PolandDepartment of Hematology, Institute of Hematology and Transfusion Medicine, Indiry Gandhi 14, 02-776 Warsaw, PolandDepartment of Immunology, Medical University of Warsaw, Nielubowicza 5 St, 02-097 Warsaw, PolandPhiladelphia 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.https://www.mdpi.com/1422-0067/21/16/5776leukemiaCMLB-ALLTKIsdrug targetsp190 |
| spellingShingle | Lukasz Komorowski Klaudyna Fidyt Elżbieta Patkowska Malgorzata Firczuk Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities International Journal of Molecular Sciences leukemia CML B-ALL TKIs drug targets p190 |
| title | Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities |
| title_full | Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities |
| title_fullStr | Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities |
| title_full_unstemmed | Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities |
| title_short | Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities |
| title_sort | philadelphia chromosome positive leukemia in the lymphoid lineage similarities and differences with the myeloid lineage and specific vulnerabilities |
| topic | leukemia CML B-ALL TKIs drug targets p190 |
| url | https://www.mdpi.com/1422-0067/21/16/5776 |
| work_keys_str_mv | AT lukaszkomorowski philadelphiachromosomepositiveleukemiainthelymphoidlineagesimilaritiesanddifferenceswiththemyeloidlineageandspecificvulnerabilities AT klaudynafidyt philadelphiachromosomepositiveleukemiainthelymphoidlineagesimilaritiesanddifferenceswiththemyeloidlineageandspecificvulnerabilities AT elzbietapatkowska philadelphiachromosomepositiveleukemiainthelymphoidlineagesimilaritiesanddifferenceswiththemyeloidlineageandspecificvulnerabilities AT malgorzatafirczuk philadelphiachromosomepositiveleukemiainthelymphoidlineagesimilaritiesanddifferenceswiththemyeloidlineageandspecificvulnerabilities |