Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6 dependent manner
(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)
- author
- 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
- organization
-
- Division of Clinical Genetics
- Translational Genomic and Functional Studies of Leukemia (research group)
- Division of Molecular Medicine and Gene Therapy
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- publishing date
- 2018
- 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
-
- pmid:28819278
- scopus:85042941323
- ISSN
- 1476-5551
- DOI
- 10.1038/leu.2017.261
- project
- Identification and characterization of candidate therapeutic targets in acute myeloid leukemia
- language
- English
- LU publication?
- yes
- id
- 896f0c0b-cd7f-4374-b953-210709fa33b1
- date added to LUP
- 2017-09-05 12:21:41
- date last changed
- 2024-09-02 06:47:06
@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}}, keywords = {{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}}, doi = {{10.1038/leu.2017.261}}, volume = {{32}}, year = {{2018}}, }