IKZF3

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 ## History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2013-08-15 : Morin : DLBCL 2019-09-26 : Panea : BL

## Relevance tier by entity

Entity	Tier	Description
	2-a	aSHM target; Although recurrent, the relevance of mutations in BL is tenuous
	1-a	aSHM target and high-confidence DLBCL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
BL	GAMBL genomes+capture	1.62
BL	Thomas cohort	0.80
BL	Panea cohort	3.00
DLBCL	GAMBL genomes	4.78
DLBCL	Schmitz cohort	4.47
DLBCL	Reddy cohort	3.90
DLBCL	Chapuy cohort	4.27

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)
BL	Yes	No	1.552
DLBCL	Yes	No	10.924
FL	Yes	No	7.180

aSHM regions

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

[!NOTE] First described in BL in 2019 by Panea RI. First described in DLBCL in 2013 by Morin RD

## 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

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

References

Lazarian, G., Yin, S., Hacken, E., Sewastianik, T., Uduman, M., Font-Tello, A., Gohil, S., Li, S., Kim, E., Joyal, H., Billington, L., Witten, E., Zheng, M., Huang, T., Severgnini, M., Lefebvre, V., Rassenti, L., Gutierrez, C., Georgopoulos, K., Ott, C., Wang, L., Kipps, T., Burger, J., Livak, K., Neuberg, D., Baran-Marszak, F., Cymbalista, F., Carrasco, R., & Wu, C. (2021). A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation.. Cancer cell, 39 3, 380-393.e8 . https://doi.org/10.1016/j.ccell.2021.02.003. ## IKZF3 Expression