Somatic Mutations in Oncogenes Are in Chronic Myeloid Leukemia Acquired De Novo via Deregulated Base-Excision Repair and Alternative Non-Homologous End Joining
Somatic mutations are a common molecular mechanism through which chronic myeloid leukemia (CML) cells acquire resistance to tyrosine kinase inhibitors (TKIs) therapy. While most of the mutations in the kinase domain of BCR-ABL1 can be successfully managed, the recurrent somatic mutations in other ge...
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Published in | Frontiers in oncology Vol. 11; p. 744373 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
20.09.2021
|
Subjects | |
Online Access | Get full text |
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Summary: | Somatic mutations are a common molecular mechanism through which chronic myeloid leukemia (CML) cells acquire resistance to tyrosine kinase inhibitors (TKIs) therapy. While most of the mutations in the kinase domain of BCR-ABL1 can be successfully managed, the recurrent somatic mutations in other genes may be therapeutically challenging. Despite the major clinical relevance of mutation-associated resistance in CML, the mechanisms underlying mutation acquisition in TKI-treated leukemic cells are not well understood. This work demonstrated
de novo
acquisition of mutations on isolated single-cell sorted CML clones growing in the presence of imatinib. The acquisition of mutations was associated with the significantly increased expression of the
LIG1
and
PARP1
genes involved in the error-prone alternative nonhomologous end-joining pathway, leading to genomic instability, and increased expression of the
UNG
,
FEN
and
POLD3
genes involved in the base-excision repair (long patch) pathway, allowing point mutagenesis. This work showed
in vitro
and
in vivo
that
de novo
acquisition of resistance-associated mutations in oncogenes is the prevalent method of somatic mutation development in CML under TKIs treatment. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors have contributed equally to this work Edited by: Swami P. Iyer, University of Texas MD Anderson Cancer Center, United States Reviewed by: Tej K. Pandita, Baylor College of Medicine, United States; Vijaya Charaka, Houston Methodist Research Institute, United States This article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology |
ISSN: | 2234-943X 2234-943X |
DOI: | 10.3389/fonc.2021.744373 |