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Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes.
Perusini, Maria Agustina; Zácková, Daniela; Kim, Taehyung; Pagnano, Katia; Pavlovsky, Carolina; Jezísková, Ivana; Kvetková, Anezka; Jurcek, Tomás; Kim, Jaeyoon; Yoo, Youngseok; Yi, Seongyoon; Lee, Hyewon; Kim, Kyoung Ha; Chang, Myunghee; Capo-Chichi, Jose-Mario; Medeiros, Jessie J F; Arruda, Andrea; Minden, Mark; Zhang, Zhaolei; Abelson, Sagi; Mayer, Jiri; Hwan Kim, Dennis Dong.
Afiliação
  • Perusini MA; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
  • Zácková D; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic.
  • Kim T; Department of Computer Science, University of Toronto, Toronto, ON, Canada.
  • Pagnano K; The Donnelly Centre for Cellular and Biomolecular Research, Donnelly Centre for Cellular & Biomolecular Research, Toronto, ON, Canada.
  • Pavlovsky C; Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil.
  • Jezísková I; Fundaleu, Buenos Aires, Argentina.
  • Kvetková A; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic.
  • Jurcek T; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic.
  • Kim J; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic.
  • Yoo Y; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
  • Yi S; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
  • Lee H; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
  • Kim KH; Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Republic of Korea.
  • Chang M; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
  • Capo-Chichi JM; Department of Internal Medicine, Center for Hematologic Malignancies, National Cancer Center, Goyang, Republic of Korea.
  • Medeiros JJF; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
  • Arruda A; Division of Hematology and Oncology, Department of Internal Medicine, Soon Chun Hyang University Seoul Hospital, Seoul, Republic of Korea.
  • Minden M; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
  • Zhang Z; National Health Insurance Service Ilsan Hospital, Ilsan, Republic of Korea.
  • Abelson S; Genome Diagnostics & Cancer Cytogenetics Laboratories, Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada.
  • Mayer J; Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • Hwan Kim DD; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Blood Adv ; 8(10): 2361-2372, 2024 May 28.
Article em En | MEDLINE | ID: mdl-38447114
ABSTRACT
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia Mielogênica Crônica BCR-ABL Positiva / Mutação Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia Mielogênica Crônica BCR-ABL Positiva / Mutação Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2024 Tipo de documento: Article