Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6-dependent manner

Leukemia. 2018 Mar;32(3):588-596. doi: 10.1038/leu.2017.261. Epub 2017 Aug 18.


Cytokines provide signals that regulate immature normal and acute myeloid leukemia (AML) cells in the bone marrow microenvironment. We here identify interleukin 4 (IL4) as a selective inhibitor of AML cell growth and survival in a cytokine screen using fluorescently labeled AML cells. RNA-sequencing of the AML cells revealed an IL4-induced upregulation of Stat6 target genes and enrichment of apoptosis-related gene expression signatures. Consistent with these findings, we found that IL4 stimulation of AML cells induced Stat6 phosphorylation and that disruption of Stat6 using CRISPR/Cas9-genetic engineering rendered cells partially resistant to IL4-induced apoptosis. To evaluate whether IL4 inhibits AML cells in vivo, we expressed IL4 ectopically in AML cells transplanted into mice and also injected IL4 into leukemic mice; both strategies resulted in the suppression of the leukemia cell burden and increased survival. Notably, IL4 exposure caused reduced growth and survival of primary AML CD34+CD38- patient cells from several genetic subtypes of AML, whereas normal stem and progenitor cells were less affected. The IL4-induced apoptosis of AML cells was linked to Caspase-3 activation. Our results demonstrate that IL4 selectively induces apoptosis of AML cells in a Stat6-dependent manner-findings that may translate into new therapeutic opportunities in AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Apoptosis* / genetics
  • Biomarkers
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Flow Cytometry
  • Gene Expression
  • Hematopoietic Stem Cells
  • Humans
  • Interleukin-4 / metabolism*
  • Interleukin-4 / pharmacology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • STAT6 Transcription Factor / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Biomarkers
  • Cytokines
  • IL4 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Tumor Suppressor Protein p53
  • Interleukin-4