Table of Contents

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

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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

pathology Collection N mutated Incidence CI
BL GAMBL without Panea 309 3 0.0060 [0,0.0145]
BL GAMBL without ICGC/Zhou 320 4 0.0063 [0,0.0149]
BL GAMBL with Panea 410 6 0.0075 [0,0.0157]
BL BLGSP 219 1 0.0046 [0,0.0135]
BL Zhou/ICGC 90 2 0.0222 [0,0.0527]
BL Panea 101 3 0.0297 [0,0.0628]

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

1.
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
2.
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
3.
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;

Citing

If you use the information or data from this site, please cite

Krysta Coyle, Kostiantyn Dreval, Daniel Hodson and Ryan D. Morin. Audit of B-cell cancer genes. Blood Adv (2025) 9 (8): 2019–2031.

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