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PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia
Y. Zhang, Y. Gao, H. Zhang, J. Zhang, F. He, A. Hnízda, M. Qian, X. Liu, Y. Gocho, CH. Pui, T. Cheng, Q. Wang, JJ. Yang, X. Zhu, X. Liu,
Language English Country United States
Document type Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
P30 CA021765
NCI NIH HHS - United States
P50 GM115279
NIGMS NIH HHS - United States
NLK
Free Medical Journals
from 1946 to 1 year ago
Freely Accessible Science Journals
from 1946 to 1 year ago
Open Access Digital Library
from 1946-01-01
Open Access Digital Library
from 1946-01-01
ROAD: Directory of Open Access Scholarly Resources
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy genetics metabolism pathology MeSH
- Angiogenic Proteins genetics MeSH
- Drug Resistance, Neoplasm genetics MeSH
- Oncogene Proteins, Fusion MeSH
- Protein Kinase Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- Mutation * MeSH
- Cell Line, Tumor MeSH
- Child, Preschool MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Recurrence MeSH
- Receptor, Platelet-Derived Growth Factor beta genetics MeSH
- Whole Genome Sequencing MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ∼10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRBC843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.
Department of Oncology St Jude Children's Research Hospital Memphis TN
Department of Pharmaceutical Sciences St Jude Children's Research Hospital Memphis TN
References provided by Crossref.org
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