New Developments in Chronic Myeloid Leukemia: Implications for Therapy.

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New Developments in Chronic Myeloid Leukemia: Implications for Therapy.

Iran J Cancer Prev. 2016 Feb;9(1):e3961

Authors: Tabarestani S, Movafagh A

Abstract
CONTEXT: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by overproduction of immature and matured myeloid cells in the peripheral blood, bone marrow and spleen.
EVIDENCE ACQUISITION: A hallmark of CML is the presence of (9; 22) (q34; q11) reciprocal translocation, which is cytogenetically visible as Philadelphia chromosome (Ph) and results in the formation of BCR-ABL1 fusion protein. This fusion protein is a constitutively active tyrosine kinase which is necessary and sufficient for malignant transformation. The introduction of imatinib, a BCR-ABL1- targeting tyrosine kinase inhibitor (TKI) has revolutionized CML therapy. Subsequently, two other TKIs with increased activity against BCR-ABL1, dasatinib and nilotinib, were developed and approved for CML patients. Nevertheless, CML therapy faces major challenges.
RESULTS: The first is the development of resistance to BCR-ABL1 inhibitors in some patients, which can be due to BCR-ABL1 overexpression, differences in cellular drug influx and efflux, activation of alternative signaling pathways, or emergence of BCR-ABL1 kinase domain mutations during TKI treatment. The second is the limited efficiency of BCR-ABL1-TKIs in blast crisis (BC) CML. The third is the insensitivity of CML stem cells to BCR-ABL1 inhibitors. Conventional chemotherapeutics and BCR-ABL1 inhibitors which act by inhibiting cell proliferation and inducing apoptosis, are ineffective against quiescent CML stem cells.
CONCLUSIONS: A better understanding of the mechanisms that underlie TKI resistance, progression to BC, genomic instability and stem cell quiescence is essential to develop curative strategies for patients with CML.

PMID: 27366312 [PubMed]

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