U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.,Nature Cell Biology

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U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2019-04-22 , DOI: 10.1038/s41556-019-0314-5
Molly A Smith _{1,

2} , Gaurav S Choudhary ₃ , Andrea Pellagatti ₄ , Kwangmin Choi ₁ , Lyndsey C Bolanos ₁ , Tushar D Bhagat ₃ , Shanisha Gordon-Mitchell ₃ , Dagny Von Ahrens ₃ , Kith Pradhan ₃ , Violetta Steeples ₄ , Sanghyun Kim ₅ , Ulrich Steidl ₃ , Matthew Walter ₅ , Iain D C Fraser ₆ , Aishwarya Kulkarni ₇ , Nathan Salomonis _{8,

9} , Kakajan Komurov _{1,

9} , Jacqueline Boultwood ₄ , Amit Verma ₃ , Daniel T Starczynowski _{1,

2,

9}

Affiliation

Spliceosome mutations are common in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but the oncogenic changes due to these mutations have not been identified. Here a global analysis of exon usage in AML samples revealed distinct molecular subsets containing alternative spliced isoforms of inflammatory and immune genes. Interleukin-1 receptor-associated kinase 4 (IRAK4) was the dominant alternatively spliced isoform in MDS and AML and is characterized by a longer isoform that retains exon 4, which encodes IRAK4-long (IRAK4-L), a protein that assembles with the myddosome, results in maximal activation of nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) and is essential for leukaemic cell function. Expression of IRAK4-L is mediated by mutant U2 small nuclear RNA auxiliary factor 1 (U2AF1) and is associated with oncogenic signalling in MDS and AML. Inhibition of IRAK4-L abrogates leukaemic growth, particularly in AML cells with higher expression of the IRAK4-L isoform. Collectively, mutations in U2AF1 induce expression of therapeutically targetable 'active' IRAK4 isoforms and provide a genetic link to activation of chronic innate immune signalling in MDS and AML.

中文翻译：

U2AF1 突变会诱导致癌 IRAK4 亚型并激活骨髓恶性肿瘤中的先天免疫途径。

剪接体突变在骨髓增生异常综合征（MDS）和急性髓系白血病（AML）中很常见，但这些突变引起的致癌变化尚未确定。这里对 AML 样本中外显子使用的全局分析揭示了包含炎症和免疫基因的替代剪接亚型的不同分子子集。白介素 1 受体相关激酶 4 (IRAK4) 是 MDS 和 AML 中主要的选择性剪接亚型，其特点是保留外显子 4 的较长亚型，编码 IRAK4 长 (IRAK4-L)，这是一种与myddosome 导致 B 细胞核因子 kappa-轻链增强子 (NF-κB) 的最大激活，对于白血病细胞功能至关重要。 IRAK4-L 的表达由突变型 U2 小核 RNA 辅助因子 1 (U2AF1) 介导，并与 MDS 和 AML 中的致癌信号传导相关。抑制 IRAK4-L 可消除白血病生长，特别是在 IRAK4-L 亚型表达较高的 AML 细胞中。总的来说，U2AF1 的突变诱导治疗上可靶向的“活性”IRAK4 同工型的表达，并提供与 MDS 和 AML 中慢性先天免疫信号激活的遗传联系。

更新日期：2019-05-16

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