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.

中文翻译：

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白细胞介素4以Stat6依赖性方式诱导急性髓性白血病细胞凋亡。

细胞因子提供调节骨髓微环境中未成熟的正常和急性髓性白血病（AML）细胞的信号。我们在这里确定白介素4（IL4）作为使用荧光标记的AML细胞的细胞因子筛选中AML细胞生长和存活的选择性抑制剂。AML细胞的RNA测序显示IL4诱导的Stat6目标基因上调和细胞凋亡相关基因表达标记的丰富。与这些发现一致，我们发现IL4刺激AML细胞诱导Stat6磷酸化，并且使用CRISPR / Cas9基因工程技术破坏Stat6使细胞部分抵抗IL4诱导的细胞凋亡。为了评估IL4是否在体内抑制AML细胞，我们在移植到小鼠的AML细胞中异位表达IL4，并且还将IL4注射到白血病小鼠中。两种策略均能抑制白血病细胞负荷并提高生存率。值得注意的是，暴露于IL4会导致原发性AML CD34的生长和存活率降低⁺ CD38 ^-从AML的几种遗传亚型，而正常干细胞和祖细胞的患者的细胞的影响较小。IL4诱导的AML细胞凋亡与Caspase-3激活有关。我们的结果表明，IL4以Stat6依赖性方式选择性诱导AML细胞凋亡，可能会转化为AML中的新治疗机会。