HMGCLL1 is a predictive biomarker for deep molecular response to imatinib therapy in chronic myeloid leukemia.
Adolescent
Adult
Aged
Aged, 80 and over
Apoptosis
Biomarkers, Tumor
/ genetics
Case-Control Studies
Cell Survival
Cohort Studies
Drug Resistance, Neoplasm
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Imatinib Mesylate
/ therapeutic use
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
/ drug therapy
Male
Middle Aged
Mutation
Oxo-Acid-Lyases
/ genetics
Prognosis
Protein Kinase Inhibitors
/ therapeutic use
Survival Rate
Tumor Cells, Cultured
Young Adult
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
30
07
2018
accepted:
16
10
2018
revised:
27
09
2018
pubmed:
18
12
2018
medline:
7
9
2019
entrez:
18
12
2018
Statut:
ppublish
Résumé
Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n = 201) and successfully replicated it in a validation set (n = 270). We also investigated the functional relevance of HMGCLL1 blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1 isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1 kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1 was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1 gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.
Identifiants
pubmed: 30555164
doi: 10.1038/s41375-018-0321-8
pii: 10.1038/s41375-018-0321-8
pmc: PMC6756062
doi:
Substances chimiques
Biomarkers, Tumor
0
Protein Kinase Inhibitors
0
Imatinib Mesylate
8A1O1M485B
Oxo-Acid-Lyases
EC 4.1.3.-
HMGCLL1 protein, human
EC 4.1.3.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1439-1450Références
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