IRF4 is a suppressor of c-Myc induced B cell leukemia

PLoS One. 2011;6(7):e22628. doi: 10.1371/journal.pone.0022628. Epub 2011 Jul 27.


Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EμMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4(+/-)Myc); the average age of mortality in the IRF4(+/-)Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4(+/-)Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4(+/-)Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27(kip) is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27(kip) was lost in the IRF4(+/-)Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27(kip) and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EμMyc mice.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Immunoglobulin M / metabolism
  • Interferon Regulatory Factors / metabolism*
  • Leukemia, B-Cell / blood
  • Leukemia, B-Cell / metabolism*
  • Leukemia, B-Cell / pathology*
  • Leukocyte Common Antigens / metabolism
  • Lymphocyte Count
  • Mice
  • Neoplasm Transplantation
  • Precursor Cells, B-Lymphoid / metabolism
  • Precursor Cells, B-Lymphoid / pathology
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism*


  • Immunoglobulin M
  • Interferon Regulatory Factors
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • interferon regulatory factor-4
  • Cyclin-Dependent Kinase Inhibitor p27
  • Leukocyte Common Antigens