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New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance

Hagop M. Kantarjian, MD; Moshe Talpaz, MD; Francis Giles, MD; Susan O'Brien, MD; and Jorge Cortes, MD
[+] Article, Author, and Disclosure Information

From MD Anderson Cancer Center, Houston, Texas, and University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.

Grant Support: None.

Potential Financial Conflicts of Interest: Grants received: H.M. Kantarjian (Novartis, Bristol-Myers Squibb), F. Giles (Novartis, Amgen, Merck & Co. Inc.), J. Cortes (Novartis, Bristol-Myers Squibb, Johnson & Johnson, Chemgenex, Breakthrough Therapeutics).

Requests for Single Reprints: Hagop M. Kantarjian, MD, Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030; e-mail, hkantarj@mdanderson.org.

Current Author Addresses: Drs. Kantarjian, Giles, O'Brien, and Cortes: Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030.

Dr. Talpaz: University of Michigan, Comprehensive Cancer Center, 1500 East Medical Center Drive, CCGC 6-303, Ann Arbor, MI 48109-0944.

Ann Intern Med. 2006;145(12):913-923. doi:10.7326/0003-4819-145-12-200612190-00008
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Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the BCR-ABL kinase fusion protein and its central role in the pathogenesis of CML provided new opportunities to develop rational molecular targeted therapies. This review provides an update on the underlying pathophysiologies of disease progression and imatinib mesylate resistance, leading to the development of new targeted tyrosine kinase inhibitors for managing CML. Imatinib, a selective inhibitor of BCR-ABL, represents a major success in the era of target-directed cancer chemotherapy. However, patients with advanced CML have been less sensitive to therapy and responses have been short. In addition, treatment resistance is an emerging problem at all disease stages. Insight into factors involved in imatinib resistance and disease progression has highlighted a role for such BCR-ABL–dependent factors as amplification and overexpression of the BCR-ABL gene and the emergence of mutant isoforms of BCR-ABL. However, BCR-ABL–independent factors, including leukemogenic pathways involving kinases other than BCR-ABL, also play a part. In light of the limitations of imatinib against these factors, newer tyrosine kinase inhibitors, including dasatinib (a multitargeted kinase inhibitor of BCR-ABL and Src family kinases) and nilotinib (AMN107, a selective BCR-ABL inhibitor), may provide promising treatment options for patients with CML.


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Figure 1.
A simplified illustration of BCR-ABL and Src family kinase involvement in oncogenic signaling pathways.

The inhibitory effect is indicated by the upside-down Ts. ABL = Abelson tyrosine kinase; BCR = breakpoint cluster region; FAK = focal adhesion kinase; Grb-2 = growth factor receptor–bound protein 2; HcK = hematopoietic cell kinase; JNK = Jun amino-terminal kinase; P = phosphate group; PI3K = phosphatidylinositol-3–kinase; SFK = Src family kinases; Stat5 = signal transducer and activator of transcription 5.

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Figure 2.
BCR-ABL characterized mutants associated with clinical resistance to imatinib.

A = activation loop; AB = actin-binding domain; ABL = Abelson tyrosine kinase; BCR = breakpoint cluster region; C = helix αC; DB = DNA-binding domain; GEF = guanine exchange factor; SH = Src homology; P = phosphate loop; S/T = serine/threonine kinase. Information in this figure is summarized from references 51, 52, 56-62. Figure reprinted with permission from reference 57: Branford S, Hughes T. Detection of BCR-ABL mutations and resistance to imatinib mesylate. In: Iland H, Hertzberg M, Marlton P, eds. Myeloid Leukemia: Methods and Protocols. Totowa, NJ: Humana Pr; 2006:93-106.

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