NSD2-epigenomic reprogramming and maintenance of plasma cell phenotype in t(4;14) myeloma

TL;DR

This study shows that NSD2 overexpression in t(4;14) myeloma affects gene expression and cell identity, influencing plasma cell markers and potentially offering new therapeutic targets.

Contribution

The study reveals NSD2's role in maintaining plasma cell identity in t(4;14) myeloma through epigenomic reprogramming.

Findings

NSD2 overexpression significantly impacts gene expression and DNA organization, particularly affecting cell identity genes.

Reduction of CD38 and other cell surface markers in NSD2 knock out cells suggests altered immunophenotype.

Plasma cell transcription factors remain unaffected, indicating NSD2 acts directly on downstream genes.

Abstract

Overexpression of the H3K36 histone methyltransferase NSD2 in t(4;14) multiple myeloma (MM) is an early, oncogenic event, and understanding its impact on genomic organisation and expression is relevant to understanding MM biology.

We performed epigenetic, transcriptional and phenotypic profiling of the t(4;14) KMS11 myeloma cell line and its isogenic translocation knock out (TKO) to characterise the sequelae of NSD2 overexpression.

We found a marked global impact of NSD2 on gene expression and DNA organisation implicating cell identity genes; notably the early lymphocyte regulator, LAIR1 and MM cell surface markers, including CD38, a classical marker of plasma cells which was reduced in TKO cells. Plasma cell transcription factors such as PRDM1, IRF4 and XBP1 were unaffected, suggesting a downstream direct gene effect of NSD2 on cell identity. Changes in cell surface markers suggest an altered surface immunophenotype.

Our findings suggest a role for NSD2 in maintaining MM cell identity, with potential implications for future therapeutic strategies based on targeting of NSD2.

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