The NSD2 p.E1099K Mutation Is Enriched at Relapse and Confers Drug Resistance in a Cell Context-Dependent Manner in Pediatric Acute Lymphoblastic Leukemia.

Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101150042 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3125 (Electronic) Linking ISSN: 15417786 NLM ISO Abbreviation: Mol Cancer Res Subsets: MEDLINE

Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002-

Drug Resistance, Neoplasm* ; Mutation*; Gene Expression Profiling/*methods ; Histone-Lysine N-Methyltransferase/*genetics ; Neoplasm Recurrence, Local/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Repressor Proteins/*genetics; Animals ; Cell Cycle ; Cell Line, Tumor ; Child ; Disease Progression ; Epigenesis, Genetic ; HEK293 Cells ; Humans ; Mice ; Sequence Analysis, RNA ; Xenograft Model Antitumor Assays

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, in vivo models using both cell lines and patient samples revealed dramatically enhanced proliferation of NSD2 EK compared with WT and reduced sensitivity to 6-mercaptopurine in the relapse sample relative to diagnosis. Finally, EK-mediated changes in chromatin state and transcriptional output differed dramatically among cell lines further supporting a cell context-specific role of NSD2 EK. These results demonstrate a unique role of NSD2 EK in mediating clonal fitness through pleiotropic mechanisms dependent on the genetic and epigenetic landscape. IMPLICATIONS: NSD2 EK mutation leads to drug resistance and a clonal advantage in childhood B-ALL.
(©2020 American Association for Cancer Research.)

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T32 CA009161 United States CA NCI NIH HHS; P30 CA016087 United States CA NCI NIH HHS; R01 CA140729 United States CA NCI NIH HHS; U10 CA180899 United States CA NCI NIH HHS; U10 CA180886 United States CA NCI NIH HHS

0 (Repressor Proteins)
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
EC 2.1.1.43 (NSD2 protein, human)

Date Created: 20200426 Date Completed: 20210702 Latest Revision: 20210702

20240829

PMC7415532

10.1158/1541-7786.MCR-20-0092

32332049