NSD1

Overview

NSD1 (Nuclear Receptor Binding SET Domain Protein 1) is a histone H3K36 methyltransferase. NSD1 is the fusion partner of NUP98 in the NUP98–NSD1 fusion, which is a recurrent oncogenic event in pediatric AML associated with adverse prognosis. The NUP98–NSD1 fusion aberrantly activates HOXA gene expression, blocking myeloid differentiation.

Alterations observed in the corpus

  • NUP98–NSD1 recurrent in-frame fusion detected by RNA-seq in adult de novo AML cases (TCGA AML cohort, 200 cases); identified as one of the additional recurrent in-frame fusions beyond the major known fusions PMID:23634996
  • NSD1 significantly mutated in 10% of HNSC (29 inactivating mutations + 4 focal homozygous deletions, MutSigCV q<0.1, TCGA n=279); H3K36 methyltransferase; loss associated with DNA hypomethylation; germline NSD1 inactivation causes Sotos syndrome with squamous-carcinoma predisposition; defines atypical and classical mRNA subtype enrichment. PMID:25631445
  • DUX4 binding at the NSD1 locus induces transcription from a non-canonical first exon in the DUX4/ERG ALL subtype, expanding the transcriptional landscape driven by the IGH–DUX4 rearrangement PMID:27776115
  • NUP98–NSD1 fusion in pediatric AML; DOT1L-inhibitor target identified in a pediatric precision-oncology cohort PMID:28007021
  • Partner gene in the NUP98-NSD1 fusion, a classic leukemic fusion recovered in LAML fusion-only tumors in pan-cancer RNA-seq fusion analysis across 9,624 TCGA samples. PMID:29617662

Cancer types (linked)

  • AML (Acute Myeloid Leukemia): NUP98–NSD1 detected in the TCGA 200-case adult AML cohort; primarily associated with pediatric and young adult AML in the broader literature, but confirmed in this adult cohort PMID:23634996

Co-occurrence and mutual exclusivity

  • NUP98–NSD1 co-occurrence with other AML drivers not specifically detailed in this study PMID:23634996

Therapeutic relevance

  • NUP98–NSD1 fusion-driven AML has adverse prognosis and may require intensified therapy; NSD1 H3K36 methyltransferase activity is a potential therapeutic target PMID:23634996

Open questions

  • The frequency of NUP98–NSD1 in this adult AML cohort and associated cooperating mutations are not individually enumerated beyond its identification as a recurrent in-frame event PMID:23634996

Sources

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