IL-3 and Oncogenic Abl Regulate the Myeloblast Transcriptome by Altering mRNA Stability

The growth factor interleukin-3 (IL-3) promotes the survival and growth of multipotent hematopoietic progenitors and stimulates myelopoiesis. It has also been reported to oppose terminal granulopoiesis and to support leukemic cell growth through autocrine or paracrine mechanisms. The degree to which IL-3 acts at the posttranscriptional level is largely unknown. We have conducted global mRNA decay profiling and bioinformatic analyses in 32Dcl3 myeloblasts indicating that IL-3 caused immediate early stabilization of hundreds of transcripts in pathways relevant to myeloblast function. Stabilized transcripts were enriched for AU-Response elements (AREs), and an ARE-containing domain from the interleukin-6 (IL-6) 3′-UTR rendered a heterologous gene responsive to IL-3-mediated transcript stabilization. Many IL-3-stabilized transcripts had been associated with leukemic transformation. Deregulated Abl kinase shared with IL-3 the ability to delay turnover of transcripts involved in proliferation or differentiation blockade, relying, in part, on signaling through the Mek/Erk pathway. These findings support a model of IL-3 action through mRNA stability control and suggest that aberrant stabilization of an mRNA network linked to IL-3 contributes to leukemic cell growth.

白细胞介素3（interleukin-3, IL-3）可促进多能造血祖细胞的存活与增殖，并刺激髓系生成。另有研究表明，其可通过自分泌或旁分泌机制抑制终末粒细胞生成，并支持白血病细胞增殖。目前学界对IL-3在转录后水平发挥调控作用的程度尚不清楚。本研究在32Dcl3骨髓母细胞中开展了全基因组mRNA降解谱分析与生物信息学研究，结果显示IL-3可即刻早期稳定数百条与骨髓母细胞功能相关通路的转录本。这些稳定的转录本富含AU应答元件（AU-Response elements, AREs）；将白细胞介素6（interleukin-6, IL-6）3'非翻译区（3′-UTR）中含ARE的结构域植入异源基因后，该基因即可对IL-3介导的转录本稳定产生响应。大量经IL-3稳定的转录本已被证实与白血病转化相关。失调的Abl激酶与IL-3类似，可延缓增殖或分化阻滞相关转录本的降解，其部分机制依赖于通过Mek/Erk信号通路进行的信号转导。上述研究结果支持了IL-3通过调控mRNA稳定性发挥作用的模型，并提示与IL-3相关的mRNA调控网络发生异常稳定，可能促进白血病细胞增殖。