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

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title = "Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6 dependent manner",
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 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.",
keywords = "Journal Article",
author = "Pablo Pe{\~n}a and Mia Eriksson and R Ramakrishnan and M Chapellier and Carl H{\"o}gberg and C Orsmark-Pietras and J Richter and Anna Andersson and T Fioretos and M J{\"a}r{\aa}s",
year = "2018",
doi = "10.1038/leu.2017.261",
language = "English",
volume = "32",
pages = "588--596",
journal = "Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K",
issn = "1476-5551",
publisher = "Nature Publishing Group",
number = "3",