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

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T1 - Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6 dependent manner

AU - Peña, Pablo

AU - Eriksson, Mia

AU - Ramakrishnan, R

AU - Chapellier, M

AU - Högberg, Carl

AU - Orsmark-Pietras, C

AU - Richter, J

AU - Andersson, Anna

AU - Fioretos, T

AU - Järås, M

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/leu.2017.261

DO - 10.1038/leu.2017.261

M3 - Article

C2 - 28819278

VL - 32

SP - 588

EP - 596

JO - Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K

JF - Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K

SN - 1476-5551

IS - 3

ER -