Rahn Kerstin, Abdallah Ali T, Gan Lin, Herbrich Shelley, Sonntag Roland, Benitez Oscar, Malaney Prerna, Zhang Xiaorui, Rodriguez Ashely G, Brottem Jared, Marx Gernot, Brümmendorf Tim H, Ostareck Dirk H, Ostareck-Lederer Antje, Crysandt Martina, Post Sean M, Naarmann-de Vries Isabel S
Department of Intensive Care Medicine, University Hospital RWTH Aachen University, Aachen, Germany; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Interdisciplinary Center for Clinical Research (IZKF) Aachen, RWTH Aachen University, Germany; Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Biochim Biophys Acta Gene Regul Mech. 2024 Mar;1867(1):195004. doi: 10.1016/j.bbagrm.2023.195004. Epub 2023 Nov 25.
Deletions on the long arm of chromosome 9 (del(9q)) are recurrent abnormalities in about 2 % of acute myeloid leukemia cases, which usually involve HNRNPK and are frequently associated with other known aberrations. Based on an Hnrnpk haploinsufficient mouse model, a recent study demonstrated a function of hnRNP K in pathogenesis of myeloid malignancies via the regulation of cellular proliferation and myeloid differentiation programs. Here, we provide evidence that reduced hnRNP K expression results in the dysregulated expression of C/EBPα and additional transcription factors. CyTOF analysis revealed monocytic skewing with increased levels of mature myeloid cells. To explore the role of hnRNP K during normal and pathological myeloid differentiation in humans, we characterized hnRNP K-interacting RNAs in human AML cell lines. Notably, RNA-sequencing revealed several mRNAs encoding key transcription factors involved in the regulation of myeloid differentiation as targets of hnRNP K. We showed that specific sequence motifs confer the interaction of SPI1 and CEBPA 5' and 3'UTRs with hnRNP K. The siRNA mediated reduction of hnRNP K in human AML cells resulted in an increase of PU.1 and C/EBPα that is most pronounced for the p30 isoform. The combinatorial treatment with the inducer of myeloid differentiation valproic acid resulted in increased C/EBPα expression and myeloid differentiation. Together, our results indicate that hnRNP K post-transcriptionally regulates the expression of myeloid master transcription factors. These novel findings can inaugurate novel options for targeted treatment of AML del(9q) by modulation of hnRNP K function.
9号染色体长臂缺失（del(9q)）是约2%急性髓系白血病病例中的常见异常，通常涉及HNRNPK，且常与其他已知畸变相关。基于一个Hnrnpk单倍体不足小鼠模型，最近一项研究表明hnRNP K通过调节细胞增殖和髓系分化程序在髓系恶性肿瘤发病机制中发挥作用。在此，我们提供证据表明hnRNP K表达降低导致C/EBPα和其他转录因子表达失调。CyTOF分析显示成熟髓系细胞水平升高导致单核细胞偏向。为了探究hnRNP K在人类正常和病理性髓系分化过程中的作用，我们对人类急性髓系白血病细胞系中与hnRNP K相互作用的RNA进行了表征。值得注意的是，RNA测序揭示了几个编码参与髓系分化调控的关键转录因子的mRNA是hnRNP K的靶点。我们表明特定序列基序赋予SPI1和CEBPA 5'和3'UTR与hnRNP K的相互作用。siRNA介导的人类急性髓系白血病细胞中hnRNP K的减少导致PU.1和C/EBPα增加，其中p30异构体最为明显。与髓系分化诱导剂丙戊酸联合治疗导致C/EBPα表达增加和髓系分化。总之，我们的结果表明hnRNP K在转录后水平调节髓系主要转录因子的表达。这些新发现可为通过调节hnRNP K功能靶向治疗急性髓系白血病del(9q)开创全新选择。
