The Hidden Pathogenesis of CML: Is BCR-ABL1 the First Event?
Purpose of Review
Identification of the BCR-ABL1 fusion oncogene in patients diagnosed with chronic myeloid leukemia (CML) led to the development of targeted therapy responsible for the dramatic survival benefits observed in the past two decades. However, despite these revolutionary findings, there remains marked disparity in patient outcomes. Why do some patients present de novo while others evolve to the more aggressive stages of CML? Why can select patients successfully discontinue therapy as part of a treatment-free remission attempt whereas others fail to meet specific molecular milestones?
BCR-ABL1 kinase mutations are only identified in approximately 50% of patients with poor responses and disease progression, suggesting the presence of alternative resistance mechanisms. Numerous institutions have identified the presence of additional genomic events in addition to BCR-ABL1 with the increasing availability of next-generation sequencing.
We explore the potential pathways and events that may cooperate with BCR-ABL1 to answer these questions but also challenge the fundamental tenet that BCR-ABL1 is always the sole event initiating CML.
KeywordsNext-generation sequencing Mutations Disease progression Resistance
N.S. received scholarship funding from the Royal Adelaide Hospital Research Foundation Dawes Scholarship. S.B. received support from the National Health and Medical Research Council of Australia (APP1104425).
Compliance with Ethical Standards
Conflict of Interest
N.S. received honoraria from Novartis and Bristol-Myers Squibb and travel and accommodation expenses from Novartis, Gilead, Amgen and Janssen. S.B. is a member of the advisory boards of Qiagen, Novartis and Bristol-Myers Squibb and received honoraria from Qiagen, Novartis, Bristol-Myers Squibb and Cepheid.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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