A role for IRF4 in the development of CLL

Vipul Shukla, Shibin Ma, Richard R. Hardy, Shantaram S Joshi, Runqing Lu

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator of B-cell development and function. A recent genome-wide single-nucleotide polymorphism (SNP) association study identified IRF4 as a major susceptibility gene in chronic lymphocytic leukemia (CLL). Although the SNPs located in the IRF4 gene were linked to a downregulation of IRF4 in CLL patients, whether a low level of IRF4 is critical for CLL development remains unclear. In rodents, CLL cells are derived from B1 cells whose population is dramatically expanded in immunoglobulin heavy chain Vh11 knock-in mice. We bred a Vh11 knock-in allele into IRF4-deficient mice (IRF4-/-Vh11). Here, we report that IRF4-/-Vh11 mice develop spontaneous early-onset CLL with 100% penetrance. Further analysis shows that IRF4-/-Vh11 CLL cells proliferate predominantly in spleen and express high levels of Mcl-1. IRF4-/-Vh11 CLL cells are resistant to apoptosis but reconstitution of IRF4 expression in the IRF4-/-Vh11 CLL cells inhibits their survival. Thus, our study demonstrates for the first time a causal relationship between low levels of IRF4 and the development of CLL. Moreover, our findings establish IRF4-/-Vh11 mice as a novel mouse model of CLL that not only is valuable for dissecting molecular pathogenesis of CLL but could also be used for therapeutic purposes.

Original languageEnglish (US)
Pages (from-to)2848-2855
Number of pages8
JournalBlood
Volume122
Issue number16
DOIs
StatePublished - Jan 1 2013

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
Genes
interferon regulatory factor-4
Single Nucleotide Polymorphism
Immunoglobulin Heavy Chains
Penetrance
Polymorphism
Rodentia
B-Lymphocytes
Down-Regulation
Spleen
Nucleotides
Alleles

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Shukla, V., Ma, S., Hardy, R. R., Joshi, S. S., & Lu, R. (2013). A role for IRF4 in the development of CLL. Blood, 122(16), 2848-2855. https://doi.org/10.1182/blood-2013-03-492769

A role for IRF4 in the development of CLL. / Shukla, Vipul; Ma, Shibin; Hardy, Richard R.; Joshi, Shantaram S; Lu, Runqing.

In: Blood, Vol. 122, No. 16, 01.01.2013, p. 2848-2855.

Research output: Contribution to journalArticle

Shukla, V, Ma, S, Hardy, RR, Joshi, SS & Lu, R 2013, 'A role for IRF4 in the development of CLL', Blood, vol. 122, no. 16, pp. 2848-2855. https://doi.org/10.1182/blood-2013-03-492769
Shukla, Vipul ; Ma, Shibin ; Hardy, Richard R. ; Joshi, Shantaram S ; Lu, Runqing. / A role for IRF4 in the development of CLL. In: Blood. 2013 ; Vol. 122, No. 16. pp. 2848-2855.
@article{bdc6e3f3f8cd43358e470d2197f9b57b,
title = "A role for IRF4 in the development of CLL",
abstract = "Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator of B-cell development and function. A recent genome-wide single-nucleotide polymorphism (SNP) association study identified IRF4 as a major susceptibility gene in chronic lymphocytic leukemia (CLL). Although the SNPs located in the IRF4 gene were linked to a downregulation of IRF4 in CLL patients, whether a low level of IRF4 is critical for CLL development remains unclear. In rodents, CLL cells are derived from B1 cells whose population is dramatically expanded in immunoglobulin heavy chain Vh11 knock-in mice. We bred a Vh11 knock-in allele into IRF4-deficient mice (IRF4-/-Vh11). Here, we report that IRF4-/-Vh11 mice develop spontaneous early-onset CLL with 100{\%} penetrance. Further analysis shows that IRF4-/-Vh11 CLL cells proliferate predominantly in spleen and express high levels of Mcl-1. IRF4-/-Vh11 CLL cells are resistant to apoptosis but reconstitution of IRF4 expression in the IRF4-/-Vh11 CLL cells inhibits their survival. Thus, our study demonstrates for the first time a causal relationship between low levels of IRF4 and the development of CLL. Moreover, our findings establish IRF4-/-Vh11 mice as a novel mouse model of CLL that not only is valuable for dissecting molecular pathogenesis of CLL but could also be used for therapeutic purposes.",
author = "Vipul Shukla and Shibin Ma and Hardy, {Richard R.} and Joshi, {Shantaram S} and Runqing Lu",
year = "2013",
month = "1",
day = "1",
doi = "10.1182/blood-2013-03-492769",
language = "English (US)",
volume = "122",
pages = "2848--2855",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "16",

}

TY - JOUR

T1 - A role for IRF4 in the development of CLL

AU - Shukla, Vipul

AU - Ma, Shibin

AU - Hardy, Richard R.

AU - Joshi, Shantaram S

AU - Lu, Runqing

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator of B-cell development and function. A recent genome-wide single-nucleotide polymorphism (SNP) association study identified IRF4 as a major susceptibility gene in chronic lymphocytic leukemia (CLL). Although the SNPs located in the IRF4 gene were linked to a downregulation of IRF4 in CLL patients, whether a low level of IRF4 is critical for CLL development remains unclear. In rodents, CLL cells are derived from B1 cells whose population is dramatically expanded in immunoglobulin heavy chain Vh11 knock-in mice. We bred a Vh11 knock-in allele into IRF4-deficient mice (IRF4-/-Vh11). Here, we report that IRF4-/-Vh11 mice develop spontaneous early-onset CLL with 100% penetrance. Further analysis shows that IRF4-/-Vh11 CLL cells proliferate predominantly in spleen and express high levels of Mcl-1. IRF4-/-Vh11 CLL cells are resistant to apoptosis but reconstitution of IRF4 expression in the IRF4-/-Vh11 CLL cells inhibits their survival. Thus, our study demonstrates for the first time a causal relationship between low levels of IRF4 and the development of CLL. Moreover, our findings establish IRF4-/-Vh11 mice as a novel mouse model of CLL that not only is valuable for dissecting molecular pathogenesis of CLL but could also be used for therapeutic purposes.

AB - Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator of B-cell development and function. A recent genome-wide single-nucleotide polymorphism (SNP) association study identified IRF4 as a major susceptibility gene in chronic lymphocytic leukemia (CLL). Although the SNPs located in the IRF4 gene were linked to a downregulation of IRF4 in CLL patients, whether a low level of IRF4 is critical for CLL development remains unclear. In rodents, CLL cells are derived from B1 cells whose population is dramatically expanded in immunoglobulin heavy chain Vh11 knock-in mice. We bred a Vh11 knock-in allele into IRF4-deficient mice (IRF4-/-Vh11). Here, we report that IRF4-/-Vh11 mice develop spontaneous early-onset CLL with 100% penetrance. Further analysis shows that IRF4-/-Vh11 CLL cells proliferate predominantly in spleen and express high levels of Mcl-1. IRF4-/-Vh11 CLL cells are resistant to apoptosis but reconstitution of IRF4 expression in the IRF4-/-Vh11 CLL cells inhibits their survival. Thus, our study demonstrates for the first time a causal relationship between low levels of IRF4 and the development of CLL. Moreover, our findings establish IRF4-/-Vh11 mice as a novel mouse model of CLL that not only is valuable for dissecting molecular pathogenesis of CLL but could also be used for therapeutic purposes.

UR - http://www.scopus.com/inward/record.url?scp=84888211403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888211403&partnerID=8YFLogxK

U2 - 10.1182/blood-2013-03-492769

DO - 10.1182/blood-2013-03-492769

M3 - Article

VL - 122

SP - 2848

EP - 2855

JO - Blood

JF - Blood

SN - 0006-4971

IS - 16

ER -