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. 2024 May 28;8(10):2361-2372.
doi: 10.1182/bloodadvances.2023012127.

Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes

Maria Agustina Perusini  1 , Daniela Žáčková  2 , Taehyung Kim  3   4 , Katia Pagnano  5 , Carolina Pavlovsky  6 , Ivana Ježíšková  2 , Anežka Kvetková  2 , Tomáš Jurček  2 , Jaeyoon Kim  1 , Youngseok Yoo  1 , Seongyoon Yi  1   7 , Hyewon Lee  1   8 , Kyoung Ha Kim  1   9 , Myunghee Chang  1   10 , Jose-Mario Capo-Chichi  11 , Jessie J F Medeiros  12   13 , Andrea Arruda  1   14 , Mark Minden  1   14   15 , Zhaolei Zhang  4   13   3 , Sagi Abelson  12   13 , Jiri Mayer  2 , Dennis Dong Hwan Kim  1   15
Affiliations

Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes

Maria Agustina Perusini et al. Blood Adv. .

Abstract

Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) toward precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifier genes and activated signaling/myeloid transcription factors (AS/MTFs) with disease progression and treatment failure in patients with CML after tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML 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%. Seventy mutations were detected in 57 diagnostic samples (22.4%), whereas 64 mutations were detected in 39 of the follow-up samples (27.9%). Carrying any mutation at initial diagnosis was associated with worse outcomes after TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with imatinib showed higher risks of treatment failure (hazard ratio, 2.53; 95% confidence interval, 1.13-5.66; P = .0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs. The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival, and progression risk. Additionally, there was an observable nonsignificant trend indicating a heightened risk of progression to advanced disease and worse overall survival. In 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 and may help upfront TKI selection.

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Conflict of interest statement

Conflict-of-interest disclosure: D.D.H.K. received honoraria from Bristol Myers Squibb and Novartis, and is involved in consultancy for Novartis, Pfizer, and Paladin. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Frequency of mutations in patients with CML by TKI therapy response. Summary of mutation frequency at diagnosis (A) and follow-up sample (B). The mutations were classified according to their biological pathway.
Figure 2.
Figure 2.
Impact of the presence of any somatic mutation on treatment outcomes after TKI therapy. Treatment outcomes include MMR, FFS, and OS. Results are shown for the overall population and imatinib-treated and 2G-TKI–treated groups.
Figure 3.
Figure 3.
Impact of the presence of mutations in AS/MTF genes on treatment outcomes after TKI therapy. Treatment outcomes include MMR, FFS, and OS. Results are shown for the overall population and imatinib-treated and 2G-TKI–treated groups.
Figure 4.
Figure 4.
Longitudinal comparison of allele burdens change according to the biologic pathway of somatic mutation between diagnosis and follow-up samples.
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