Introduction

The hallmark of chronic myeloid leukemia (CML) is the presence of a balanced translocation, t(9;22)(q34;q11.2), known as the Philadelphia (Ph) chromosome (1,2). This juxtaposes two genes, ABL, which encodes a protein with tyrosine kinase activity, and BCR, which encodes a protein with serine kinase activity. The result is a fusion gene, BCR-ABL, which upon translation gives rise to a fusion protein with increased tyrosine kinase activity. Imatinib mesylate (Gleevecâ„¢) has become standard therapy in CML with complete hematologic response (CHR) in 98% and complete cytogenetic response (CCyR) in 87%, with a survival free from transformation of 93% after 60 months of follow-up among patients treated in early chronic phase (CP) in the IRIS trial (3). However, a subset of patients have either primary or secondary resistance to imatinib. Several mechanisms of resistance have been identified in these patients. The most common mechanism of resistance is the development of mutations in the Abl kinase domain, but other mechanisms have been identified, including overexpression or amplification of BCR-ABL or its protein product, disruption of the transport of imatinib into the cells or increased transport out of the cells, and BCR-ABL-independent mechanisms such as the overexpression of Src-related kinases. These are described in more detail in Chapter 7. Several strategies are being investigated in order to overcome imatinib resistance, including the development of novel tyrosine kinase inhibitors with enhanced activity against Bcr-Abl compared to imatinib and/or inhibitory activity against other kinases that modulate downstream Bcr-Abl signaling pathways.

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