Brendel Cornelia, Teichler Sabine, Millahn Axel, Stiewe Thorsten, Krause Michael, Stabla Kathleen, Ross Petra, Huynh Minh, Illmer Thomas, Mernberger Marco, Barckhausen Christina, Neubauer Andreas
Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Clinic Giessen and Marburg, Marburg, Germany.
Molecular Oncology, Philipps University of Marburg, Marburg, Germany.
PLoS One. 2015 Apr 22;10(4):e0123181. doi: 10.1371/journal.pone.0123181. eCollection 2015.
RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS, as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog (MEIS1) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies.
RAS突变在急性髓系白血病（AML）患者中经常被发现，产生一种组成型激活的信号蛋白，改变细胞增殖、分化和凋亡。我们之前已经表明，用大剂量阿糖胞苷治疗AML患者对那些携带致癌性RAS的患者特别有益。基于小鼠AML细胞培养模型，我们将这种效应归因于RAS驱动的、p53依赖的分化诱导。因此，在本研究中，我们试图证实RAS状态与从AML患者获得的原代母细胞分化之间的相关性。通过基因集富集分析（GSEA）和对一组独特的AML患者的髓系亲嗜性病毒整合位点1同源物（MEIS1）进行实时PCR分析表明，与具有野生型RAS的母细胞相比，具有致癌性NRAS的AML母细胞的基因表达特征确实对应于更成熟的谱型。此外，用已建立的细胞系和另一组原发性AML细胞进行的体外细胞培养实验表明，致癌性NRAS突变使细胞易于发生阿糖胞苷（AraC）驱动的分化。综上所述，我们的研究结果表明，伴有inv(16)和NRAS突变的AML具有分化基因特征，支持NRAS突变可能使白血病细胞易于发生AraC诱导分化的观点。因此，我们认为特定基因改变对分化途径的促进作用可以解释某些AML患者亚组治疗后更好的治疗结果。分化基因表达状态是否通常可以预测AML更好的治疗结果需要在未来的研究中加以探讨。
