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December 8, 2025BloodOpen Access

Dynamic mutational evolution and transcriptomic remodeling on 3rd-generation TKI therapy in TKI-resistant patients with chronic myeloid leukemia

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Authors

XZXiaoshuai ZhangZLZongru LiYQYa-Zhen Qin

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Overview

Longitudinal analysis reveals TKI therapy alters gene expression and clonal architecture in chronic myeloid leukemia, suggesting novel resistance mechanisms.

Key Points

  • This research aims to elucidate the molecular dynamics during 3G-TKI therapy in CML patients and the mechanisms driving resistance.
  • Analyzed 202 CML patients receiving 3G-TKIs.
  • Collected baseline and serial blood samples for sequencing analysis.
  • Classified mutational dynamics via variant allele frequency trajectories.
  • Performed multi-machine learning and unsupervised clustering on gene expression profiles.
  • Characterized biological transitions through pathway enrichment and immune deconvolution.
  • Identified significant declines in mutations in responders, while resistant patients showed persistent clones.
  • Transcriptomic remodeling indicated down-regulation of leukemic stem cells and activation of immune pathways in responders.
  • Defined three molecular subtypes with distinct therapy responses and outcomes based on gene expression profiles.

Cite This Study

Zhang et al. (2025) studied this question.

synapsesocial.com/papers/69362f7f4fa91c937236e5a3https://doi.org/10.1182/blood-2025-5540
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Genetic evolution in CML patients from diagnosis to TKI failure: An analysis of 121 paired diagnosis and treatment failure samples2025
  2. 2Impact of Somatic Mutations on Treatment Response and Resistance in Chronic Myeloid Leukemia2026
  3. 3Systematic molecular profiling to identify determinants of response to ibrutinib2025
  4. 4Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses2026 · 2 citations
  5. 5Abstract 5917: Single-cell profiling of NK cells in chronic myeloid leukemia identifies distinct cell states with gene regulatory signatures associated with differential outcomes after imatinib discontinuation2026