Distinct biological impact of dephosphorylation vs. downregulation of p210^Bcr-Abl: Implications for imatinib mesylate response and resistance

Abstract

Imatinib mesylate suppresses phosphorylation of its kinase target, Bcr-Abl. We hypothesized that loss of p210^Bcr-Abl (the kinase target) may lead to imatinib mesylate resistance. We studied K562 cells [chronic myelogenous leukemia (CML) blast crisis line] and MO7E/MBA-1 cells (with MBA-1 cells representing MO7E cells stably transfected with BCR-ABL). Imatinib mesylate resistance developed when p210^Bcr-Abl expression was abolished. Furthermore, K562 cells were significantly more growth suppressed after imatinib mesylate exposure than after downregulation of Bcr-Abl expression. Signaling pathways which were functional in the absence of Bcr-Abl expression (NF-κB and mitogen-activated protein kinase activation or the growth factor pathway) were disrupted when p210^Bcr-Abl was present but dephosphorylated, suggesting that an intact, but enzymatically inactive Bcr-Abl, may interfere with critical growth/signaling pathways. Downregulation of p210^Bcr-Abl may be a mechanism by which imatinib mesylate resistance emerges. Samples from three of 15 patients with imatinib mesylate-resistant CML blast crisis had undetectable levels of p210^Bcr-Abl. We conclude that retention of a dephosphorylated p210^Bcr-Abl has a biologic impact distinct from that of downregulation/loss of p210^Bcr-Abl and, in a subset of patients, loss of the target of the kinase inhibitor may lead to imatinib mesylate resistance.

Keywords:

• Bcr-Abl
• leukemia
• Philadelphia chromosome
• imatinib mesylate
• kinase