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Targeting Epigenetic Processes in CML Cells

By: Sarah Campen, PharmD
Posted: Tuesday, September 10, 2019

Although the development and pathogenesis of chronic myeloid leukemia (CML) are well understood in a genetic context, the importance of epigenetic reprogramming at various stages of CML progression and in response to therapy is just now being identified. In a review article published in Frontiers in Cell and Developmental Biology, David Vetrie, PhD, of the University of Glasgow, United Kingdom, and colleagues discussed these epigenetic alterations and the potential of epigenetic therapies as a means of eradicating residual disease in combination with current therapies.

“Further understanding of epigenetic processes is required to overcome many clinical issues which still exist in CML, such as the optimal treatment of patients in more developed stages of the disease, the prerequisites for treatment discontinuation, and the factors involved in the survival of [leukemic stem cells],” explained Dr. Vetrie and colleagues.

A number of processes are involved in the epigenetic reprogramming of CML cells. They include dysregulation of EZH1 and EZH2, BCL6, BMI1, and SIRT1; DNA methylation; non-coding RNAs; and mutations in ASXL1. All of these are believed to contribute to the survival of bulk CML and leukemic stem cells or disease progression.

A number of epigenetic therapies that target these processes have been proposed and may result in eradication of CML cells in combination with tyrosine kinase inhibitor therapy. Evidence from blast phase cell lines suggests BCL6 may be a survival factor, indicating that BCL6 inhibitors may be effective in the treatment of both the accelerated and blast phases of disease.  Several other epigenetic therapies are currently in clinical trials for oncologic indications as well and have shown promise in murine models.

“Evolving technologies such as whole-genome sequencing, single-cell RNA sequencing, and genome-wide DNA methylation will aid in the further development of the role of epigenetics in CML, and the promise of epigenetic therapies,” concluded the authors.

Disclosure: The study authors reported no conflicts of interest.



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