The NSD2 p.E1099K Mutation Is Enriched at Relapse and Confers Drug Resistance in a Cell Context-Dependent Manner in Pediatric Acute Lymphoblastic Leukemia.
Animals
Cell Cycle
Cell Line, Tumor
Child
Disease Progression
Drug Resistance, Neoplasm
Epigenesis, Genetic
Gene Expression Profiling
/ methods
HEK293 Cells
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Mice
Mutation
Neoplasm Recurrence, Local
/ genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
Repressor Proteins
/ genetics
Sequence Analysis, RNA
Xenograft Model Antitumor Assays
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
27
01
2020
revised:
10
03
2020
accepted:
17
04
2020
pubmed:
26
4
2020
medline:
3
7
2021
entrez:
26
4
2020
Statut:
ppublish
Résumé
The NSD2 p.E1099K (EK) mutation is observed in 10% of acute lymphoblastic leukemia (ALL) samples with enrichment at relapse indicating a role in clonal evolution and drug resistance. To discover mechanisms that mediate clonal expansion, we engineered B-precursor ALL (B-ALL) cell lines (Reh, 697) to overexpress wildtype (WT) and EK NSD2, but observed no differences in proliferation, clonal growth, or chemosensitivity. To address whether NSD2 EK acts collaboratively with other pathways, we used short hairpin RNAs to knockdown expression of NSD2 in B-ALL cell lines heterozygous for NSD2 EK (RS4;11, RCH-ACV, SEM). Knockdown resulted in decreased proliferation in all lines, decreased clonal growth in RCH-ACV, and increased sensitivity to cytotoxic chemotherapeutic agents, although the pattern of drug sensitivity varied among cell lines implying that the oncogenic properties of NSD2 mutations are likely cell context specific and rely on cooperative pathways. Knockdown of both Type II and REIIBP EK isoforms had a greater impact than knockdown of Type II alone, suggesting that both SET containing EK isoforms contribute to phenotypic changes driving relapse. Furthermore,
Identifiants
pubmed: 32332049
pii: 1541-7786.MCR-20-0092
doi: 10.1158/1541-7786.MCR-20-0092
pmc: PMC7415532
mid: NIHMS1587498
doi:
Substances chimiques
Repressor Proteins
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
NSD2 protein, human
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1153-1165Subventions
Organisme : NCI NIH HHS
ID : T32 CA009161
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016087
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA140729
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180899
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180886
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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