Young David J, Stoddart Angela, Nakitandwe Joy, Chen Shann-Ching, Qian Zhijian, Downing James R, Le Beau Michelle M
Department of Pediatrics, Division of Oncology, Johns Hopkins University, Baltimora, MD.
Department of Medicine and the Comprehensive Cancer Center, University of Chicago, IL
Haematologica. 2014 Jun;99(6):1032-40. doi: 10.3324/haematol.2013.098657. Epub 2014 Feb 14.
The control of mRNA stability plays a central role in orchestrating gene-regulatory networks in hematopoietic cell growth, differentiation and tumorigenesis. HNRNPA0, which encodes an RNA-binding protein shown to regulate transcript stability via binding to the AU-rich elements of mRNAs, is located within the commonly deleted segment of 5q31.2 in myeloid neoplasms with a del(5q), and is expressed at haploinsufficient levels in these patients. We show that HNRNPA0 is normally highly expressed in hematopoietic stem cells and exhibits dynamic changes in expression during the course of differentiation. To model HNRNPA0 haploinsufficiency, we used RNAi interference in primary murine cells and an experimental cell system, and found that reduced Hnrnpa0 expression leads to a shift from monocytic towards granulocytic differentiation. Microarray-based global expression profiling revealed that Hnrnpa0 knockdown disproportionally impacts AU-rich containing transcripts and alters expression of myeloid specification genes. In therapy-related myeloid neoplasms with a del(5q), AU-rich containing mRNAs are enriched in transcripts that encode proteins associated with increased growth and proliferation. Our findings implicate haploinsufficiency of HNRNPA0 as one of the key initiating mutations in the pathogenesis of myeloid neoplasms with a del(5q), and suggest that therapies that target AU-rich elements warrant consideration in efforts to develop new mechanism-based treatment strategies.
mRNA稳定性的调控在协调造血细胞生长、分化和肿瘤发生过程中的基因调控网络中起着核心作用。HNRNPA0编码一种RNA结合蛋白，该蛋白可通过与mRNA的富含AU元件结合来调节转录本稳定性，它位于伴有5号染色体长臂缺失（del(5q)）的髓系肿瘤中常见的5q31.2缺失区段内，且在这些患者中以单倍剂量不足水平表达。我们发现，HNRNPA0在造血干细胞中通常高度表达，并在分化过程中表现出表达的动态变化。为模拟HNRNPA0单倍剂量不足，我们在原代鼠细胞和一个实验性细胞系统中使用了RNAi干扰，发现Hnrnpa0表达降低会导致细胞从单核细胞分化向粒细胞分化转变。基于微阵列的全基因组表达谱分析显示，敲低Hnrnpa0对富含AU的转录本有不成比例的影响，并改变髓系特异性基因的表达。在伴有del(5q)的治疗相关髓系肿瘤中，富含AU的mRNA在编码与生长和增殖增加相关蛋白质的转录本中富集。我们的研究结果表明，HNRNPA0单倍剂量不足是伴有del(5q)的髓系肿瘤发病机制中的关键起始突变之一，并提示在开发基于新机制的治疗策略时，靶向富含AU元件的疗法值得考虑。
