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Maintaining Low BCR-ABL Signaling Output to Restrict CML Progression and Enable Persistence

Maintaining Low BCR-ABL Signaling Output to Restrict CML Progression and Enable Persistence Deregulated BCR-ABL oncogenic activity leads to transformation, oncogene addiction and drives disease progression in chronic myeloid leukemia (CML). Inhibition of BCR-ABL using Abl-specific kinase inhibitors (TKI) such as imatinib induces remarkable clinical responses. However, approximately only less than 15 % of all chronic-phase CML patients will remain relapse-free after discontinuation of imatinib in deep molecular remission. It is not well understood why persisting CML cells survive under TKI therapy without developing clonal evolution and frank TKI resistance. BCR-ABL expression level may be critically involved. Whereas higher BCR-ABL expression has been described as a pre-requisite for malignant CML stem cell transformation and CML progression to blast crisis, recent evidence suggests that during persistence TKI select for CML precursors with low BCR-ABL expression. Genetic, translational and clinical evidence is discussed to suggest that TKI-induced maintenance of low BCR-ABL signaling output may be potently tumor suppressive, because it abrogates oncogenic addiction. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Hematologic Malignancy Reports Springer Journals

Maintaining Low BCR-ABL Signaling Output to Restrict CML Progression and Enable Persistence

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References (98)

Publisher
Springer Journals
Copyright
Copyright © 2014 by The Author(s)
Subject
Medicine & Public Health; Hematology; Oncology; Geriatrics/Gerontology
ISSN
1558-8211
eISSN
1558-822X
DOI
10.1007/s11899-013-0196-8
pmid
24500518
Publisher site
See Article on Publisher Site

Abstract

Deregulated BCR-ABL oncogenic activity leads to transformation, oncogene addiction and drives disease progression in chronic myeloid leukemia (CML). Inhibition of BCR-ABL using Abl-specific kinase inhibitors (TKI) such as imatinib induces remarkable clinical responses. However, approximately only less than 15 % of all chronic-phase CML patients will remain relapse-free after discontinuation of imatinib in deep molecular remission. It is not well understood why persisting CML cells survive under TKI therapy without developing clonal evolution and frank TKI resistance. BCR-ABL expression level may be critically involved. Whereas higher BCR-ABL expression has been described as a pre-requisite for malignant CML stem cell transformation and CML progression to blast crisis, recent evidence suggests that during persistence TKI select for CML precursors with low BCR-ABL expression. Genetic, translational and clinical evidence is discussed to suggest that TKI-induced maintenance of low BCR-ABL signaling output may be potently tumor suppressive, because it abrogates oncogenic addiction.

Journal

Current Hematologic Malignancy Reports – Springer Journals

Published: Feb 6, 2014

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