De Novo Acquisition of BCR-ABL Mutations for CML Acquired Resistance

Abstract

Chronic myelogenous leukemia (CML) is a rare and fatal neoplastic disease clinically presented as aberrant accumulation of myeloid cells in bone marrow, blood and spleen. CML occurs in 1 to 2 cases per 100,000 people, and is most common in older people with a median age at diagnosis of around 65. In the United States of America, there are 3500 to 5000 new cases per year (Jemal et al., 2010). If untreated, CML naturally progresses from initial chronic phase to accelerated phase and blast crisis that resembles acute myeloid leukemia. CML is one of the most extensively studied human cancers, and exemplifies that good scientific research can lead to successful treatment of a devastating disease. In early 1960s, a characteristic small chromosome of CML was identified by Peter Nowell and David Hungerford who worked in University of Pennsylvania and Fox Chase Cancer Center in Philadelphia, respectively, and was subsequently called the Philadelphia (Ph) chromosome (Nowell and Hungerford, 1960; Nowell and Hungerford, 1961). Ph chromosome is found in 95% CML patients. In 1973, Janet Rowley identified that Ph chromosome was a product of reciprocal translocation of chromosome 9 and 22, the t(9;22)(q34;q11) (Rowley, 1973). In early 1980s, the genes involved in translocation were identified as proto-oncogene ABL (human homolog of Abelson leukemia virus gene) on chromosome 9 that was fused to BCR (break cluster region) on chromosome 22 (Groffen et al., 1984), revealing molecular insight of CML. In early 1990s, aberrant tyrosine kinase activity of BCR-ABL and its essential roles in transformation of cells were established by several groups (Daley et al., 1990; Heisterkamp et al., 1990; Lugo et al., 1990). These molecular discoveries provide crucial foundation for drug development for CML treatment. In 1996, Brian Druker and colleagues reported the first specific ABL kinase inhibitor imatinib mesylate (STI571, CGP 57148, or Gleevec) that effectively inhibited growth of BCRABL positive cells (Druker et al., 1996). In 1998, a phase I clinical trial of imatinib was initiated in three centers in the United States (Druker et al., 2001). Imatinib shows magnificent effect on bringing CML patients, especially those in chronic phase, into remission and improving long-term survival and disease management (Druker et al., 2006), and the drug is now the first line treatment for CML. However, in contrast to chronic CML, patients at advanced phases (accelerated phase and blast crisis) generally have only transient response to imatinib, and relapse quickly (Deininger and Druker, 2003). Even for chronic phase patients, imatinib does not eradicate the disease and it relapses rapidly if imatinib is discontinued (Michor et al., 2005). Multiple