updates

## Overview

This is one of several genes that encode linker histone proteins that are recurrently mutated in DLBCL and FL.^1,2 Mutations are often found in the globular domain of the protein, which is critical for its interaction with DNA and other histone proteins.

## History

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## Overview

This is one of several genes that encode linker histone proteins that are recurrently mutated in DLBCL and FL.<sup>1,2</sup> Mutations are often found in the globular domain of the protein, which is critical for its interaction with DNA and other histone proteins.

## History

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# HIST1H2AC

This gene encodes the H2A protein, one of the core proteins comprising nucleosomes. Although relatively common in DLBCL, little is known about the function of these mutations.

## History

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## Overview

HVCN1, a voltage-gated proton channel, has been identified as recurrently mutated in follicular lymphoma and mutations also appear in some DLBCL.<sup>1</sup> HVCN1 mutations disrupt its normal function, affecting B-cell receptor (BCR) signaling pathways.<sup>1</sup> This gene has some recurrent sites of mutations (hot spots) but the function of these mutations is not well understood. The mutation pattern in DLBCL and FL implies the preferential accumulation of *inactivating mutations*.

## History

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## Overview

IKZF3 (IKAROS family zinc finger 3, also known as AIOLOS) is a transcription factor involved in regulating B-cell development and function. Mutations in IKZF3 can lead to transcriptional dysregulation and contribute to the pathogenesis of B-cell neoplasms. IKZF3 is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. IKZF3 has multiple hot spot mutations in DLBCL. The most common, L162R, has been identified as a driver in CLL. In that context, it alters DNA binding specificity and causes hyperactivation of B-cell receptor (BCR) signaling and overexpression of NF-κB target genes.<sup>1</sup> While primarily studied in CLL, the functional effects of IKZF3 mutations could have implications for other B-cell malignancies, including DLBCL

## History

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## Overview

Mutations in IL4R have been identified in various types of B-cell lymphomas, particularly primary mediastinal large B-cell lymphoma (PMBCL) and DLBCL. IL4R is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. IL4R mutations are found in approximately 24.2% of primary PMBCL cases. These mutations are commonly single nucleotide variants in exon 8, resulting in the I242N amino acid change. This leads to constitutive activation of the JAK-STAT signaling pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens.<sup>1,2</sup> In DLBCL, IL4R mutations are more rare and tend to occur within the GCB subgroup.<sup>2</sup>

## History

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## Overview

IRF4 (Interferon Regulatory Factor 4) encodes a transcription factor that plays a critical role in the regulation of immune response genes and B-cell development. Mutations and rearrangements in the IRF4 gene have been implicated in various B-cell lymphomas, including DLBCL. IRF4-rearranged large B-cell lymphomas (LBCL-IRF4) show a unique molecular profile with strong expression of IRF4/MUM1 and are associated with favorable outcomes. MUM1 staining is also commonly used to assign DLBCLs to one of the two cell-of-origin (COO) subgroups by immunohistochemistry.<sup>1</sup> IRF4 is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. There are a few mutation hotspots in this gene. The functional role of mutations in IRF4 in the absence of a rearrangement remains poorly understood.

## History

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## Overview

IRF8 (Interferon Regulatory Factor 8) is a transcription factor critical for the development and function of B lymphocytes. Mutations in IRF8 have been implicated in various lymphoid malignancies, most predominantly in FL and DLBCL. IRF8 is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. Coding and non-coding mutations in IRF8 are associated with the EZB subgroup of DLBCL.<sup>1</sup> There is preliminary evidence that IRF8 mutations contribute to immune evasion by downregulating CD74 and HLA-DM in DLBCL.<sup>2</sup> These are crucial for processing and presentation of self antigens.

## History

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## Overview

The ITPKB gene encodes inositol-trisphosphate 3-kinase B, an enzyme involved in the regulation of intracellular calcium levels and PI3K/Akt signaling pathways. Mutations in ITPKB have been linked to various B-cell lymphomas, including DLBCL, PMBCL and, less commonly, FL.<sup>1</sup> ITPKB is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. These mutations are associated with the **BN2** genetic subgroup of DLBCL. The mutation pattern in ITPKB implies selection for loss-of-function mutations.

## History

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