The Hidden Pathogenesis of CML: Is BCR-ABL1 the First Event?

  • Naranie ShanmuganathanEmail author
  • Susan Branford
Chronic Myeloid Leukemias (G Saglio, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Chronic Myeloid Leukemias


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?

Recent Findings

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.


Next-generation sequencing Mutations Disease progression Resistance 


Funding Information

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Naranie Shanmuganathan
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  • Susan Branford
    • 1
    • 2
    • 3
    • 6
    • 7
  1. 1.Department of Genetics and Molecular PathologySA PathologyAdelaideAustralia
  2. 2.Precision Medicine ThemeSouth Australian Health and Medical Research InstituteAdelaideAustralia
  3. 3.School of MedicineUniversity of AdelaideAdelaideAustralia
  4. 4.Department of HaematologyRoyal Adelaide Hospital and SA PathologyAdelaideAustralia
  5. 5.School of Health SciencesUniversity of South AustraliaAdelaideAustralia
  6. 6.School of Pharmacy and Medical ScienceUniversity of South AustraliaAdelaideAustralia
  7. 7.School of Biological SciencesUniversity of AdelaideAdelaideAustralia

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