Somatic mutations in myeloid transcription factors and in activated signaling genes predict the risk of treatment failure and progression to advanced phase in chronic myeloid leukemia

Abstract

Abstract Background Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) towards precision medicine. The impact of epigenetic modifier gene mutations on treatment outcomes is still under debate. Here we studied the association of somatic mutations in the genes of epigenetic modifiers and activated signaling/myeloid transcription factor (AS/MTF), with disease progression and treatment failure in CML patients following tyrosine kinase inhibitor (TKI) therapy. Patients and Methods: A total of 394 CML patient samples were sequenced, including 254 samples collected at initial diagnosis, and 140 samples taken during follow-up. Single molecule molecular inversion probe (smMIP)-based next generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes with a limit of detection of 0.2%. Results A total of 70 mutations were detected in 57 (22.4%) diagnostic samples, while 64 mutations were detected in 39 (27.9%) of the follow-up samples. Carrying any mutation at initial diagnosis was associated with worse outcomes following TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with Imatinib showed higher risks of treatment failure (HR 2.53, 95% CI [1.13–5.66], p = 0.0239). The adverse prognostic impact of the mutations was abrogated when treated with second generation TKIs (2G-TKI). The multivariate analysis confirmed that mutation in AS/MF genes is an independent adverse prognostic factor for molecular response, failure-free survival (FFS), and progression risk. Conclusion Mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression, even from initial diagnosis, and may help upfront TKI selection.