Naarmann-de Vries Isabel S, Sackmann Yvonne, Klein Felicitas, Ostareck-Lederer Antje, Ostareck Dirk H, Jost Edgar, Ehninger Gerhard, Brümmendorf Tim H, Marx Gernot, Röllig Christoph, Thiede Christian, Crysandt Martina
Department of Intensive Care Medicine, University Hospital RWTH Aachen University, Aachen, Germany.
Department of Intensive Care Medicine, University Hospital RWTH Aachen University, Aachen, Germany; Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen University, Aachen, Germany.
Leuk Res. 2019 Jan;76:15-23. doi: 10.1016/j.leukres.2018.11.007. Epub 2018 Nov 17.
Acute myeloid leukemia is an aggressive disease that arises from clonal expansion of malignant hematopoietic precursor cells of the bone marrow. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of acute myeloid leukemia patients. Our deletion analysis in a cohort of 31 del(9q) acute myeloid leukemia patients further supports the importance of a minimally deleted region composed of seven genes potentially involved in leukemogenesis: GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2. Importantly, among them HNRNPK, encoding heterogeneous nuclear ribonucleoprotein K is proposed to function in leukemogenesis. We show that expression of HNRNPK and the other genes of the minimally deleted region is significantly reduced in patients with del(9q) compared with normal karyotype acute myeloid leukemia. Also, two mRNAs interacting with heterogeneous nuclear ribonucleoprotein K, namely CDKN1A and CEBPA are significantly downregulated. While the deletion size is not correlated with outcome, associated genetic aberrations are important. Patients with an additional t(8;21) show a good prognosis. RUNX1-RUNX1T1, which emerges from the t(8;21) leads to transcriptional down-regulation of CEBPA. Acute myeloid leukemia patients with mutations in CEBPA have a good prognosis as well. Interestingly, in del(9q) patients with CEBPA mutation mRNA levels of HNRNPK and the other genes located in the minimally deleted region is restored to normal karyotype level. Our data indicate that a link between CEBPA and the genes of the minimally deleted region, among them HNRNPK contributes to leukemogenesis in acute myeloid leukemia with del(9q).
急性髓系白血病是一种侵袭性疾病，起源于骨髓恶性造血前体细胞的克隆性扩增。在2%的急性髓系白血病患者中观察到9号染色体长臂缺失（del(9q)）。我们对31例del(9q)急性髓系白血病患者的缺失分析进一步支持了一个最小缺失区域的重要性，该区域由七个可能参与白血病发生的基因组成：GKAP1、KIF27、C9ORF64、HNRNPK、RMI1、SLC28A3和NTRK2。重要的是，其中编码异质性核核糖核蛋白K的HNRNPK被认为在白血病发生中起作用。我们发现，与正常核型急性髓系白血病患者相比，del(9q)患者中HNRNPK和最小缺失区域的其他基因的表达显著降低。此外，与异质性核核糖核蛋白K相互作用的两个mRNA，即CDKN1A和CEBPA也显著下调。虽然缺失大小与预后无关，但相关的基因畸变很重要。伴有额外t(8;21)的患者预后良好。由t(8;21)产生的RUNX1-RUNX1T1导致CEBPA的转录下调。CEBPA发生突变的急性髓系白血病患者预后也良好。有趣的是，在具有CEBPA突变的del(9q)患者中，HNRNPK和位于最小缺失区域的其他基因的mRNA水平恢复到正常核型水平。我们的数据表明，CEBPA与最小缺失区域的基因之间的联系，其中包括HNRNPK，在伴有del(9q)的急性髓系白血病的白血病发生中起作用。
