Targeting BCR-ABL

Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disease that accounts for 15% of all adult leukemias and is characterized by the clonal expansion of cells carrying the Philadelphia (Ph) chromosome.¹

The Ph chromosome—caused by the translocation of genes from chromosomes 9 and 22—triggers the production of the chimeric protein BCR-ABL.^1,2

It is now well recognized that the BCR-ABL protein is not only the initial cause, but also the singular driver of this disease throughout its course. This makes it an attractive target for therapeutic intervention.³

BCR-ABL Structure and Function²

The Ph chromosome is a result of a mutation that joins a portion of the human homologue of the Abelson murine leukemia (ABL) gene from chromosome 9 to the breakpoint cluster (BCR) region of chromosome 22
The chimeric protein BCR-ABL includes the tyrosine kinase region of ABL, which produces a cytokine-independent signal
BCR-ABL is thus an active tyrosine kinase, triggering cell proliferation and other downstream effects

The Philadelphia Chromosome

BCR-ABL - attractive target for CML therapeutic intervention

The Philadelphia chromosome results when a piece of chromosome
#9 switches places with a piece of chromosome #22. The translocation
forms an extra-long chromosome *9 (called der 9) and an extra-
short chromosome that contains the abnormal, fused BCR-ABL gene.

Specific Tyrosine Kinase Inhibition to Effectively Target BCR-ABL

The development of tyrosine kinase inhibitors (TKIs) that specifically target BCR-ABL has revolutionized the prognosis of CML⁴
Tyrosine kinase inhibitors work by blocking the ATP binding site located on the kinase domain of BCR-ABL, effectively preventing ATP from binding^4,5
Effective BCR-ABL inhibition is primarily based on 2 key features associated with agents that effectively target the tyrosine kinase

—High degree of affinity for the target, which is associated with more potent BCR-ABL suppression leading to hematologic response, cytogenetic response, molecular response, disease remission, and increased overall survival^5,6

—Improved binding and specificity for BCR-ABL, which also reduce the likelihood of unwanted side effects⁶

Learn more about a 1^st Line Prescription Treatment for Ph+ CML

Learn more about a 2^nd Line Prescription Treatment for Ph+ CML

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia v.1.2009. http://www.nccn.org/professionals/physician_gls? PDF/cml/pdf. Accessed September 30, 2008.
Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med. 2007;357(3):258-265.
Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105(7):2640-2653.
Goldman JM. How I treat chronic myeloid leukemia in the imatinib era. Blood. 2007;110(8):2828-2837.
Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303-2309.
Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome npositive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540-3546.