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25793396
Identification of genes transcriptionally responsive to the loss of MLL fusions in MLL-rearranged acute lymphoblastic leukemia.

PLoS One, 2015;10(3):e0120326.

van der Linden MH[1], Seslija L[1], Schneider P[1], Driessen EM[1], Castro PG[1], Stumpel DJ[1], van Roon E[1], de Boer J[2], Williams O[2], Pieters R[3], Stam RW[1]

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PMID: 25793396DOI: 10.1371/journal.pone.0120326

Impact factor: 3.752

Abstract
introduction: 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.
methods: 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.
results: 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.
conclusion: 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.
MeSH terms
Adult; Cell Line, Tumor; Child, Preschool; Cluster Analysis; DNA Methylation; Female; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Humans; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins, Fusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; RNA, Small Interfering; Transcriptome; Translocation, Genetic
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