van der Linden Marieke H, Seslija Lidija, Schneider Pauline, Driessen Emma M C, Castro Patricia Garrido, Stumpel Dominique J P M, van Roon Eddy, de Boer Jasper, Williams Owen, Pieters Rob, Stam Ronald W
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
Molecular Haematology and Cancer Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom.
PLoS One. 2015 Mar 20;10(3):e0120326. doi: 10.1371/journal.pone.0120326. eCollection 2015.
MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions.
For this, we performed gene expression profiling after siRNA-mediated repression of MLL-AF4, MLL-ENL, and AF4-MLL in MLL-rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples.
Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were affected in response to the repression of AF4-MLL showed significant enrichment in gene expression profiles associated with AF4-MLL expressing t(4;11)+ infant ALL patient samples.
We conclude that the here identified genes readily responsive to the loss of MLL fusion expression potentially represent attractive therapeutic targets and may provide additional insights in MLL-rearranged acute leukemias.
婴儿（<1岁）中MLL重排的急性淋巴细胞白血病（ALL）的特征是复发率高且预后不良。为了促进新型治疗靶点的发现，我们在此寻找受各种MLL融合抑制直接影响的基因。
为此，我们在MLL重排的ALL细胞系模型中，对MLL-AF4、MLL-ENL和AF4-MLL进行siRNA介导的抑制后进行基因表达谱分析。将获得的结果与各种已建立的基因特征进行比较，包括那些由已知的MLL-AF4靶基因组成的特征，或与原发性MLL重排的婴儿ALL样本相关的特征。
响应MLL-AF4和MLL-ENL抑制而下调的基因，在原发性MLL重排的婴儿ALL样本中表现出特征性表达，并且通常代表已知的MLL-AF4靶基因。响应MLL-AF4和MLL-ENL抑制而上调的基因，通常代表在MLL重排的婴儿ALL中因启动子高甲基化而通常沉默的基因。响应AF4-MLL抑制而受影响的基因，在与表达AF4-MLL的t(4;11)+婴儿ALL患者样本相关的基因表达谱中显示出显著富集。
我们得出结论，此处鉴定出的对MLL融合表达缺失有反应的基因，可能代表有吸引力的治疗靶点，并可能为MLL重排的急性白血病提供更多见解。
