Nagel Stefan, Pommerenke Claudia, MacLeod Roderick A F, Meyer Corinna, Kaufmann Maren, Fähnrich Silke, Drexler Hans G
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Oncotarget. 2019 May 14;10(35):3227-3247. doi: 10.18632/oncotarget.26929.
Recently, we have presented a scheme, termed "NKL-code", which describes physiological expression patterns of NKL homeobox genes in early hematopoiesis and in lymphopoiesis including main stages of T-, B- and NK-cell development. Aberrant activity of these genes underlies the generation of hematological malignancies notably T-cell leukemia. Here, we searched for deregulated NKL homeobox genes in main entities of T-cell lymphomas comprising angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), NK/T-cell lymphoma (NKTL) and peripheral T-cell lymphoma (PTCL). Our data revealed altogether 19 aberrantly overexpressed genes in these types, demonstrating deregulated NKL homeobox genes involvement in T-cell lymphomas as well. For detailed analysis we focused on NKL homeobox gene MSX1 which is normally expressed in NK-cells. MSX1 was overexpressed in subsets of HSTL patients and HSTL-derived sister cell lines DERL-2 and DERL-7 which served as models to characterize mechanisms of deregulation. We performed karyotyping, genomic and expression profiling, and whole genome sequencing to reveal mutated and deregulated gene candidates, including the fusion gene CD53-PDGFRB. Subsequent knockdown experiments allowed the reconstruction of an aberrant network involved in MSX1 deregulation, including chromatin factors AUTS2 and mutated histone HIST1H3B(K27M). The gene encoding AUTS2 is located at chromosome 7q11 and may represent a basic target of the HSTL hallmark aberration i(7q). Taken together, our findings highlight an oncogenic role for deregulated NKL homeobox genes in T-cell lymphoma and identify MSX1 as a novel player in HSTL, implicated in aberrant NK- and T-cell differentiation.
最近，我们提出了一种名为“NKL编码”的方案，该方案描述了NKL同源框基因在早期造血和淋巴细胞生成中的生理表达模式，包括T细胞、B细胞和NK细胞发育的主要阶段。这些基因的异常活性是血液系统恶性肿瘤特别是T细胞白血病产生的基础。在此，我们在T细胞淋巴瘤的主要类型中寻找失调的NKL同源框基因，这些类型包括血管免疫母细胞性T细胞淋巴瘤（AITL）、间变性大细胞淋巴瘤（ALCL）、成人T细胞白血病/淋巴瘤（ATLL）、肝脾T细胞淋巴瘤（HSTL）、NK/T细胞淋巴瘤（NKTL）和外周T细胞淋巴瘤（PTCL）。我们的数据总共揭示了这些类型中19个异常过表达的基因，表明失调的NKL同源框基因也参与了T细胞淋巴瘤。为了进行详细分析，我们聚焦于通常在NK细胞中表达的NKL同源框基因MSX1。MSX1在HSTL患者亚组以及HSTL来源的姐妹细胞系DERL-2和DERL-7中过表达，这两个细胞系用作表征失调机制的模型。我们进行了核型分析、基因组和表达谱分析以及全基因组测序，以揭示突变和失调的候选基因，包括融合基因CD53-PDGFRB。随后的敲低实验使得能够重建参与MSX1失调的异常网络，包括染色质因子AUTS2和突变的组蛋白HIST1H3B(K27M)。编码AUTS2的基因位于7号染色体7q11，可能代表HSTL标志性畸变i(7q)的一个基本靶点。综上所述，我们的研究结果突出了失调的NKL同源框基因在T细胞淋巴瘤中的致癌作用，并确定MSX1是HSTL中的一个新参与者，与异常的NK细胞和T细胞分化有关。
