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Therapy Resistance and Disease Progression in CML: Mechanistic Links and Therapeutic Strategies

  • Chronic Myeloid Leukemias (V Oehler, Section Editor)
  • Published:
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Abstract

Purpose of Review

Despite the adoption of tyrosine kinases inhibitors (TKIs) as molecular targeted therapy in chronic myeloid leukemia, some patients do not respond to treatment and even experience disease progression. This review aims to give a broad summary of advances in understanding of the mechanisms of therapy resistance, as well as management strategies that may overcome or prevent the emergence of drug resistance. Ultimately, the goal of therapy is the cure of CML, which will also require an increased understanding of the leukemia stem cell (LSC).

Recent Findings

Resistance to tyrosine kinase inhibitors stems from a range of possible causes. Mutations of the BCR-ABL1 fusion oncoprotein have been well-studied. Other causes range from cell-intrinsic factors, such as the inherent resistance of primitive stem cells to drug treatment, to mechanisms extrinsic to the leukemic compartment that help CML cells evade apoptosis.

Summary

There exists heterogeneity in TKI response among different hematopoietic populations in CML. The abundances of these TKI-sensitive and TKI-insensitive populations differ from patient to patient and contribute to response heterogeneity. It is becoming clear that targeting the BCR-ABL1 kinase through TKIs is only one part of the equation, and TKI usage alone may not cure the majority of patients with CML. Considerable effort should be devoted to targeting the BCR-ABL1-independent mechanisms of resistance and persistence of CML LSCs.

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Acknowledgements

We are grateful to insightful discussions with Dr. Vaidehi Krishnan.

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This work is funded in part by grants MOH-CSASI18may-0002 and MOH-CIRG20nov-0003 from the Singapore Ministry of Health.

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  1. Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, 8 College Road, Singapore, Singapore, 169857

    John Joson Ng & S. Tiong Ong

  2. Department of Haematology, Singapore General Hospital, Singapore, Singapore

    S. Tiong Ong

  3. Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

    S. Tiong Ong

  4. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    S. Tiong Ong

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Ng, J.J., Ong, S.T. Therapy Resistance and Disease Progression in CML: Mechanistic Links and Therapeutic Strategies. Curr Hematol Malig Rep 17, 181–197 (2022). https://doi.org/10.1007/s11899-022-00679-z

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