BCR-ABL

The expression of BCR-ABL fusion protein in tumor cells promotes tumor growth and increases resistance to apoptosis.

Role in cancer

BCR-ABL is a tyrosine kinase fusion protein, and is the result of the chromosomal translocation that produces the Philadelphia chromosome¹
BCR-ABL is expressed in tumor cells, and most frequently observed in chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and with less frequency (0.5%-3%) in acute myeloid leukemia (AML)^2-4
BCR-ABL expressing cells have increased DNA damage and genetic aberrations²

This is further associated with the generation of genetic instability²

BCR-ABL is constitutively active in cancers like CML, ALL and occasionally AML, and converts ATP to ADP^4-6

BCR-ABL expression promotes tumor cell proliferation and increases their resistance to apoptosis⁷
Preclinical data using a mouse model of CML have shown that BCR-ABL may lead to the premature release of myeloid cells in the bone marrow, further contributing to the pathogenesis of CML⁸

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Preclinical evidence

Preclinical evidence suggests that inhibiting BCR-ABL expression may suppress anti-apoptotic activity and make CML cells more susceptible to apoptosis by antileukemic agents⁹
In preclinical studies, inhibition of BCR-ABL and other signaling pathways, such as MAPK, have shown to enhance tumor cell regression, and promote an antitumor immune response⁹

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REFERENCES–BCR-ABL

1. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-2541. 2. Burke BA, Carroll M. BCR-ABL: a multi-faceted promoter of DNA mutation in chronic myelogeneous leukemia. Leukemia. 2010;24(6):1105-1112.
3. López-Andrade B, Sartori F, Gutiérrez A, et al. Acute lymphoblastic leukemia with e1a3 BCR/ABL fusion protein. A report of two cases. Exp Hematol Oncol. 2015;5:21. doi:10.1186/s40164-016-0049-y. 4. Neuendorff NR, Burmeister T, Dörken B, Westermann J. BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features. Ann Hematol. 2016;95(8):1211-1221. 5. Hantschel O. Structure, regulation, signaling, and targeting of abl kinases in cancer. Genes Cancer. 2012;3(5-6):436-446. 6. Cuellar S, Vozniak M, Rhodes J, Forcello N, Olszta D. BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. J Oncol Pharm Pract. 2018;24(6):433-452. 7. Greuber EK, Smith-Pearson P, Wang J, Pendergast AM. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer. 2013;13(8):559-571. 8. Pelletier SD, Hong DS, Hu Y, Liu Y, Li S. Lack of the adhesion molecules P-selectin and intercellular adhesion molecule-1 accelerate the development of BCR/ABL-induced chronic myeloid leukemia-like myeloproliferative disease in mice. Blood. 2004;104(7):2163-2171. 9. La Rosée P, O’Dwyer ME, Druker BJ. Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective. Leukemia. 2002;16(7):1213-1219. 10. Mumprecht S, Schürch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009;114(8):1528-1536. 11. Manlove LS, Schenkel JM, Manlove KR, et al. Heterologous vaccination and checkpoint blockade synergize to induce antileukemia immunity. J Immunol. 2016;196(11):4793-4804.