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Background: Chronic myeloid leukemia (CML), a blood cancer, is caused by translocation between chromosomes 22 and 9 that gives rises to fusion oncogene BCR-ABL. In 20th century, CML was a deadly disease, but tyrosine kinase inhibitors (TKI) led to complete remission in over 80% CML patients. Nevertheless, TKIs are expensive, and discontinuation of treatment is required in patients with very stable treatment response. As no molecular markers of durable TKI response exist, this study was conducted to find out molecular determinants of durable response in CML patients treated with TKIs.
Methods: Peripheral blood and clinical data were collected from CML patients with durable treatment response, along with appropriate controls. DNA was extracted and whole exome sequencing (WES) carried out to screen novel genes mutated only in experimental groups and absent in control groups. Mutations were confirmed using Sanger sequencing. Data was analyzed using SPSS version 23.
Results: Although WES detected 10 genes mutated exclusively in CML patients with durable treatment response, Sanger sequencing could confirm mutations only in RAI1 gene (GC deletion at nucleotides 837-838, a frameshift mutation).
Conclusions: Our study shows that mutations in a novel gene (RAI1) are associated with durable response in CML patients. RAI1 gene is active throughout the body and controls functions of many genes involved in daily rhythms. Our studies provide first important insights into molecular factors associated with long-term treatment response in CML that can serve as novel biomarker to identify patients eligible for TKI cessation in many ongoing CML STOP-TKI trials.
Zafar Iqbal. (2022) Investigations on molecular determinants of durable molecular response in chronic myeloid leukemia patients, Advancements in Life Sciences, Volume 9, Issue 1.
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