IKZF3

Table of Contents

Overview
Experimental Evidence
Relevance tier by entity
Mutation incidence in large patient cohorts (GAMBL reanalysis)
- DLBCL
- BL
Mutation pattern and selective pressure estimates
aSHM regions
IKZF3 Hotspots
Expression
References

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 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.¹ While primarily studied in CLL, the functional effects of IKZF3 mutations could have implications for other B-cell malignancies, including DLBCL

Experimental Evidence

Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).¹

Relevance tier by entity

Entity	Tier	Description
	2	Role of IKZF3 mutations in BL requires confirmation
	1	High-confidence DLBCL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity	Collection	N	mutated	Incidence	95% CI
DLBCL	GAMBL without Reddy	1,089	44	0.0404	[0.0287,0.0521]
DLBCL	GAMBL with Reddy	2,088	83	0.0398	[0.0314,0.0481]
DLBCL	BC	231	6	0.0260	[0.0055,0.0465]
DLBCL	Dana-Farber	303	13	0.0429	[0.0201,0.0657]
DLBCL	NCI	470	21	0.0447	[0.026,0.0634]
DLBCL	Reddy	999	39	0.0390	[0.027,0.051]
DLBCL	DLBCL_ICGC	85	4	0.0471	[0.002,0.0921]

BL

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Mutation pattern and selective pressure estimates

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aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chr17	37928959	37940119	TSS-1	NA
chr17	38015776	38024832	TSS-2	NA

IKZF3 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr17	37948968	T>C	I128V
chr17	37948958	T>C	N131S
chr17	37948950	T>C	M134V
chr17	37948949	A>T	M134K
chr17	37947783	T>G	N160H
chr17	37947782	T>C	N160S
chr17	37947776	A>C	L162R
chr17	37944583	G>T	Q213K
chr17	37944582	T>C	Q213R
chr17	37944577	T>G	S215R
chr17	37944575	A>T	S215R
chr17	37944575	A>C	S215R
chr17	37944568	C>T	E218K
chr17	37944565	C>T	E219K
chr17	37944564	T>A	E219V
chr17	37944556	C>T	E222K

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Expression

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References

Lazarian G, Yin S, Ten Hacken E, Sewastianik T, Uduman M, Font-Tello A, Gohil SH, Li S, Kim E, Joyal H, Billington L, Witten E, Zheng M, Huang T, Severgnini M, Lefebvre V, Rassenti LZ, Gutierrez C, Georgopoulos K, Ott CJ, Wang L, Kipps TJ, Burger JA, Livak KJ, Neuberg DS, Baran-Marszak F, Cymbalista F, Carrasco RD, Wu CJ. A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation. Cancer Cell. 2021 Mar 8;39(3):380–393.e8. PMCID: PMC8034546

Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff RD, Scott DW, Ding J, Roth A, Chiu R, Corbett RD, Chan FC, Mendez-Lago M, Trinh DL, Bolger-Munro M, Taylor G, Hadj Khodabakhshi A, Ben-Neriah S, Pon J, Meissner B, Woolcock B, Farnoud N, Rogic S, Lim EL, Johnson NA, Shah S, Jones S, Steidl C, Holt R, Birol I, Moore R, Connors JM, Gascoyne RD, Marra MA. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood. 2013 Aug 15;122(7):1256–1265. PMCID: PMC3744992

Panea R, Love C, Shingleton JR, Reddy A, Bailey J, Moormann A, Otieno J, Ong’echa J, Oduor C, Schroêder K, Masalu N, Chao N, Agajanian M, Major M, Fedoriw Y, Richards K, Rymkiewicz G, Miles R, Alobeid B, Bhagat G, Flowers C, Ondrejka S, Hsi E, Choi W, Au-Yeung R, Hartmann W, Lenz G, Meyerson H, Lin YY, Zhuang Y, Luftig M, Waldrop A, Dave T, Thakkar D, Sahay H, Li G, Palus B, Seshadri V, Kim S, Gascoyne R, Levy S, Mukhopadhyay M, Dunson D, Dave S. The whole genome landscape of Burkitt lymphoma subtypes. Blood. 2019;