Molecular and Therapeutic Clues in Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) originates from pluripotent hematopoietic stem cells that acquire translocation between the BCR gene on chromosome 22 and the ABL proto-oncogene on chromosome 9. Such rearrangement leads to the the Philadelphia (Ph) chromosome and the oncogenic fusion protein formation. This oncoprotein induces cell proliferation, causes abnormal migration, and reduces apoptosis. The suppression of BCR-ABL protein with imatinib and other specific tyrosine kinase inhibitors (TKIs) has revolutionized CML treatment and is currently regarded as the gold standard of targeted cancer therapy. However, drug resistance to anti-cancer chemotherapy is a significant barrier to the treatment of leukemia patients. Many times, resistance results from molecular adaptation to drug exposure, such as genetic mutation of key enzymes, upregulation of pro-survival compensatory signaling pathways, and altered drug transport. In this chapter, we reviewed the literature on the CML molecular biology, molecular targeted agents and their mechanisms of resistance.

Keywords: Leukemia, resistance, TKIs, BCR-ABL, Philadelphia (Ph) chromosome, leukemia stem cells (LSCs), imatinib.