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

PERUSINI, Maria Agustina, Daniela ŽÁČKOVÁ, TaeHyung KIM, Katia B B PAGNANO, Carolina PAVLOVSKY, Ivana JEŽÍŠKOVÁ, Anežka KVETKOVÁ, Tomáš JURČEK, Jaeyoon John KIM, Young Seok YOO, Seongyoon YI, Hyewon LEE, Kyoung Ha KIM, Myunghee CHANG, Capo-Chichi JOSE-MARIO, Jessie MEDEIROS, Andrea ARRUDA, Mark D MINDEN, Zhaolei ZHANG, Sagi ABELSON, Jiří MAYER and Dennis Dong Hwan KIM. Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes. Blood advances. AMSTERDAM: ELSEVIER, 2024. ISSN 2473-9529. Available from: https://dx.doi.org/10.1182/bloodadvances.2023012127.

Basic information

• Original name: Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes
• Authors: PERUSINI, Maria Agustina, Daniela ŽÁČKOVÁ, TaeHyung KIM, Katia B B PAGNANO, Carolina PAVLOVSKY, Ivana JEŽÍŠKOVÁ, Anežka KVETKOVÁ, Tomáš JURČEK, Jaeyoon John KIM, Young Seok YOO, Seongyoon YI, Hyewon LEE, Kyoung Ha KIM, Myunghee CHANG, Capo-Chichi JOSE-MARIO, Jessie MEDEIROS, Andrea ARRUDA, Mark D MINDEN, Zhaolei ZHANG, Sagi ABELSON, Jiří MAYER and Dennis Dong Hwan KIM.
• Edition: Blood advances, AMSTERDAM, ELSEVIER, 2024, 2473-9529.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30205 Hematology
• Country of publisher: Netherlands
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 7.500 in 2022
• Organization unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1182/bloodadvances.2023012127
• UT WoS: 999
• Keywords in English: Myeloid Neoplasia
• Tags: 14110212
• Tags: International impact, Reviewed

Abstract

Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) towards precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifiers genes and activated signaling/myeloid transcription factor (AS/MTF), with disease progression and treatment failure in CML patients following 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%. 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 not clear for patients treated with second-generation TKIs (2G-TKI). The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival (FFS), and progression risk. Additionally, there was an observable non-significant trend indicating a heightened risk of progression to advanced disease and worse overall survival (OS). 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.