Muris J J F, Ylstra B, Cillessen S A G M, Ossenkoppele G J, Kluin-Nelemans J C, Eijk P P, Nota B, Tijssen M, de Boer W P H, van de Wiel M, van den Ijssel P R L A, Jansen P, de Bruin P C, van Krieken J H J M, Meijer G A, Meijer C J L M, Oudejans J J
Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
Br J Haematol. 2007 Jan;136(1):38-47. doi: 10.1111/j.1365-2141.2006.06375.x. Epub 2006 Oct 25.
Intrinsic resistance of lymphoma cells to apoptosis is a probable mechanism causing chemotherapy resistance and eventual fatal outcome in patients with diffuse large B cell lymphomas (DLBCL). We investigated whether microarray expression profiling of apoptosis related genes predicts clinical outcome in 46 patients with primary nodal DLBCL. Unsupervised cluster analysis using genes involved in apoptosis (n = 246) resulted in three separate DLBCL groups partly overlapping with germinal centre B-lymphocytes versus activated B-cells like phenotype. One group with poor clinical outcome was characterised by high expression levels of pro-and anti-apoptotic genes involved in the intrinsic apoptosis pathway. A second group, also with poor clinical outcome, was characterised by high levels of apoptosis inducing cytotoxic effector genes, possibly reflecting a cellular cytotoxic immune response. The third group showing a favourable outcome was characterised by low expression levels of genes characteristic for both other groups. Our results suggest that chemotherapy refractory DLBCL are characterised either by an intense cellular cytotoxic immune response or by constitutive activation of the intrinsic mediated apoptosis pathway with concomitant downstream inhibition of this apoptosis pathway. Consequently, strategies neutralising the function of apoptosis-inhibiting proteins might be effective as alternative treatment modality in part of chemotherapy refractory DLBCL.
淋巴瘤细胞对凋亡的内在抗性可能是弥漫性大B细胞淋巴瘤（DLBCL）患者化疗耐药及最终导致致命结局的一种机制。我们研究了凋亡相关基因的微阵列表达谱是否能预测46例原发性淋巴结DLBCL患者的临床结局。使用参与凋亡的基因（n = 246）进行无监督聚类分析，结果产生了三个不同的DLBCL组，部分与生发中心B淋巴细胞与活化B细胞样表型重叠。一组临床结局较差的特征是参与内在凋亡途径的促凋亡和抗凋亡基因高表达。第二组临床结局也较差，其特征是凋亡诱导细胞毒性效应基因水平较高，这可能反映了细胞毒性免疫反应。显示良好结局的第三组的特征是其他两组所特有的基因低表达。我们的结果表明，化疗难治性DLBCL的特征要么是强烈的细胞毒性免疫反应，要么是内在介导的凋亡途径的组成性激活以及该凋亡途径的下游抑制。因此，中和凋亡抑制蛋白功能的策略可能作为部分化疗难治性DLBCL的替代治疗方式有效。
