more DLBCL

# IRF4

## 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.¹ 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.

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# IRF8

## 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.¹ There is preliminary evidence that IRF8 mutations contribute to immune evasion by downregulating CD74 and HLA-DM in DLBCL.² These are crucial for processing and presentation of self antigens.

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# ITPKB

## 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.¹ 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.

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# ITPR3

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|:------:|:----:|--------------------------------------|

| |2 |relevance in BL not firmly established|

## Mutation incidence in large patient cohorts (GAMBL reanalysis)

<!-- ORIGIN: loveGeneticLandscapeMutations2012 -->

<!-- BL: loveGeneticLandscapeMutations2012 -->

<!-- BL: loveGeneticLandscapeMutations2012 -->

# JAK1

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<!-- ORIGIN: zhangGeneticHeterogeneityDiffuse2013 -->

<!-- DLBCL: zhangGeneticHeterogeneityDiffuse2013 -->

<!-- PMBL: mottokIntegrativeGenomicAnalysis2019b -->

# JAK3

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<!-- ORIGIN: zhangGeneticHeterogeneityDiffuse2013 -->

<!-- DLBCL: zhangGeneticHeterogeneityDiffuse2013 -->

# JUNB

## Overview

JUNB has been reported to be frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL).¹ Mutations have also been reported in DLBCL but the mutation rate in the earliest study² was likely an over-estimate.³ According to one study, mutations are often enriched at somatic hypermutation hotspot sites, indicating the involvement of aberrant somatic hypermutation in the pathogenesis of these lymphomas.¹

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## History

Mutations in this gene were first described in FL in 2021 by Hübschmann et al.¹

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# KCMF1

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<!-- ORIGIN: reddyGeneticFunctionalDrivers2017 -->

<!-- DLBCL: reddyGeneticFunctionalDrivers2017 -->

# KCNK10

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<!-- ORIGIN: paneaWholeGenomeLandscape2019 -->

<!-- BL: paneaWholeGenomeLandscape2019 -->

# KIFC3

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<!-- ORIGIN: loveGeneticLandscapeMutations2012 -->

<!-- BL: loveGeneticLandscapeMutations2012 -->

# KLF2

## Overview

KLF2 (Kruppel-like factor 2) is a transcription factor involved in the regulation of various cellular processes, including apoptosis, proliferation, and differentiation. Mutations in KLF2 have been identified in various B-cell lymphomas including DLBCL.¹ KLF2 mutations are among the most common mutations in splenic marginal zone lymphoma (SMZL).² KLF2 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.³ KLF2 mutations have been shown to impair the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR, and TNFR signaling, thereby promoting lymphomagenesis. This implicates KLF2 as a tumor suppressor in B-cell lymphomas.² Contradictory to this, the mutation pattern in DLBCL implies selective pressure to retain a full-length protein.

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# KLHL14

## Overview

KLHL14 (Kelch-like family member 14) is a gene that has been identified as playing a role in B-cell lymphomas, particularly diffuse large B-cell lymphoma (DLBCL).¹ KLHL14 has been identified as a recurrent target of somatic mutations in ABC DLBCLs. These mutations are a feature of the MCD genetic subgroup of DLBCL. The gene encodes a protein involved in the ubiquitin-proteasome system, and its inactivation leads to increased cell proliferation and survival, suggesting its role as a tumor suppressor.² KLHL14 loss has been shown to BCR-dependent NF-κB activation and cell survival in DLBCL.² This gene has some mutation hotspots but the patter of mutation overall is consistent with its role as a tumor suppressor gene.

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# KLHL21

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<!-- ORIGIN: schmitzGeneticsPathogenesisDiffuse2018a -->

<!-- DLBCL: schmitzGeneticsPathogenesisDiffuse2018a -->

# KLHL26

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<!-- ORIGIN: burkhardtClinicalRelevanceMolecular2022b -->

<!-- BL: burkhardtClinicalRelevanceMolecular2022b -->

KLHL6 mutations appear to be relatively common in DLBCL, FL and possibly BL.¹ KLHL6 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. KLHL6 mutations lead to the loss of its function as part of a cullin-RING ubiquitin ligase complex.

KLHL6 is considered a tumor suppressor gene in DLBCL with mutations tending to disrupt its interaction with cullin3, leading to the loss of its ligase activity.²

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|:------:|:----:|--------------------------------------|

| |1-a | aSHM target and high-confidence DLBCL gene |

| |1-a | aSHM target and high-confidence FL gene |

| |2-a | aSHM target; Although recurrent, the relevance of mutations in BL is tenuous |

# KRAS

## Overview

KRAS mutations are rare but occur in some cases of DLBCL.¹ These often affect the most common KRAS hotspot sites that are mutated in other solid cancers (G12 and G13).

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# LAMA5

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<!-- ORIGIN: schmitzGeneticsPathogenesisDiffuse2018a -->

<!-- DLBCL: schmitzGeneticsPathogenesisDiffuse2018a -->

# LPP

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<!-- ORIGIN: arthurGenomewideDiscoverySomatic2018 -->

<!-- DLBCL: arthurGenomewideDiscoverySomatic2018 -->

# LTB

## Overview

LTB (Lymphotoxin Beta) is a member of the tumor necrosis factor (TNF) superfamily, which plays a role in the development and organization of secondary lymphoid tissues and in the regulation of immune responses. LTB 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. Although the mutation incidence is relatively high in DLBCL, little is known about the role of these mutations in lymphomagenesis. The mutation pattern overall implies a selective pressure to acquire loss-of-function mutations in LTB.

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