Advanced

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

Peña, Pablo LU ; Eriksson, Mia LU ; Ramakrishnan, R LU ; Chapellier, M LU ; Högberg, Carl LU ; Orsmark-Pietras, C LU ; Richter, J LU ; Andersson, Anna LU ; Fioretos, T LU and Järås, M LU (2018) In Leukemia 32(3). p.588-596
Abstract

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... (More)

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.Leukemia accepted article preview online, 18 August 2017. doi:10.1038/leu.2017.261.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
Leukemia
volume
32
issue
3
pages
588 - 596
publisher
Nature Publishing Group
external identifiers
  • scopus:85042941323
ISSN
1476-5551
DOI
10.1038/leu.2017.261
language
English
LU publication?
yes
id
896f0c0b-cd7f-4374-b953-210709fa33b1
date added to LUP
2017-09-05 12:21:41
date last changed
2018-10-17 21:34:23
@article{896f0c0b-cd7f-4374-b953-210709fa33b1,
  abstract     = {<p>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.Leukemia accepted article preview online, 18 August 2017. doi:10.1038/leu.2017.261.</p>},
  author       = {Peña, Pablo and Eriksson, Mia and Ramakrishnan, R and Chapellier, M and Högberg, Carl and Orsmark-Pietras, C and Richter, J and Andersson, Anna and Fioretos, T and Järås, M},
  issn         = {1476-5551},
  keyword      = {Journal Article},
  language     = {eng},
  number       = {3},
  pages        = {588--596},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6 dependent manner},
  url          = {http://dx.doi.org/10.1038/leu.2017.261},
  volume       = {32},
  year         = {2018},
}