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[Cancer Research 64, 672-677, January 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Imatinib Mesylate Resistance Through BCR-ABL Independence in Chronic Myelogenous Leukemia

Nicholas J. Donato1, Ji Y. Wu1, Jonathan Stapley1, Hui Lin2, Ralph Arlinghaus2, Bharat Aggarwal1, Shishir Shishodin1, Maher Albitar3, Kimberly Hayes4, Hagop Kantarjian5 and Moshe Talpaz1

1 Departments of Bioimmunotherapy,
2 Molecular Pathology,
3 Hematopathology,
4 Cytogenetics, and
5 Leukemia, University of Texas, M. D. Anderson Cancer Center, Houston, Texas

Imatinib mesylate (IM) binds to the BCR-ABL protein, inhibiting its kinase activity and effectively controlling diseases driven by this kinase. IM resistance has been associated with kinase mutations or increased BCR-ABL expression. However, disease progression may be mediated by other mechanisms that render tumor cells independent of BCR-ABL. To demonstrate this potential, IM-resistant cells were found in chronic myelogenous leukemia patients with continuous BCR-ABL gene expression but undetectable BCR-ABL protein expression. These cells were unresponsive to IM and acquired BCR-ABL-independent signaling characteristics. IM resistance in some patients may be mediated through loss of kinase target dependence.




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