High frequency of point mutations clustered within the adenosine triphosphate–binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance

Abstract

Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph ؉ ALL) and imatinib resistance (defined as loss of established hematologic response), but they were found in only 1 of 10 patients with CML with imatinib refractoriness (failure to achieve cytogenetic response). In 10 of 10 patients for whom samples were available, the mutation was not detected before the initiation of imatinib therapy.

Fusion tyrosine kinases: a result and cause of genomic instability

“…However, clinical and experimental observations reveal that resistance to the drug has become a rising problem (Weisberg and Griffin, 2001;Gorre and Sawyers, 2002). Resistance may be achieved by enhanced expression of the kinase (Mahon et al, 2000;Gorre and Sawyers, 2002;Hochhaus et al, 2002), blocking of the drug (Gambacorti-Passerini et al, 2000), reduction of cellular concentration of the drug (Mahon et al, 2003) and also by mutations in the BCR/ABL gene (Mahon et al, 2000;Branford et al, 2002;Gorre and Sawyers, 2002;Hofmann et al, 2002;Azam et al, 2003). The latter phenomenon appears to play a major role in IM resistance of Ph þ leukemias (Hochhaus et al, 2002); however, the mechanisms causing mutations are not known.…”

Imatinib mesylate‐sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: Report of two cases

“…Several mechanisms have been proposed to account for the loss of sensitivities to imatinib mesylate, including clonal evolution, amplification and mutations of the BCR-ABL gene, overexpression of BCR-ABL, and development of a multidrug resistance phenotype [7][8][9][10][11][12]. On the other hand, imatinib mesylate inhibits proliferation of blastic clones in some patients [3,13].…”

Cancer treatment with kinase inhibitors: what have we learnt from imatinib?

“…In a separate study (Branford et al, 2002), only one out of 10 CML patients with primary resistance to imatinib therapy had a BCR-ABL mutation, suggesting that a different mechanism is responsible in this setting.…”

“…This mechanism has perhaps been most widely studied and appears to be the most common mechanism of resistance in clinical practice (Gorre et al, 2001;Branford et al, 2002;Hochhaus et al, 2002;Shah et al, 2002;Branford et al, 2003).…”