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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.

SUBMITTER: Pena-Martinez P 

PROVIDER: S-EPMC5843897 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Peña-Martínez P P   Eriksson M M   Ramakrishnan R R   Chapellier M M   Högberg C C   Orsmark-Pietras C C   Richter J J   Andersson A A   Fioretos T T   Järås M M  

Leukemia 20170818 3


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 stimulati  ...[more]

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