title: Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias.
abstract: Important biological and pathologic properties are often conserved across species. Although several mouse leukemia models have been well established, the genes deregulated in both human and murine leukemia cells have not been studied systematically. We performed a serial analysis of gene expression in both human and murine MLL-ELL or MLL-ENL leukemia cells and identified 88 genes that seemed to be significantly deregulated in both types of leukemia cells, including 57 genes not reported previously as being deregulated in MLL-associated leukemias. These changes were validated by quantitative PCR. The most up-regulated genes include several HOX genes (e.g., HOX A5, HOXA9, and HOXA10) and MEIS1, which are the typical hallmark of MLL rearrangement leukemia. The most down-regulated genes include LTF, LCN2, MMP9, S100A8, S100A9, PADI4, TGFBI, and CYBB. Notably, the up-regulated genes are enriched in gene ontology terms, such as gene expression and transcription, whereas the down-regulated genes are enriched in signal transduction and apoptosis. We showed that the CpG islands of the down-regulated genes are hypermethylated. We also showed that seven individual microRNAs (miRNA) from the mir-17-92 cluster, which are overexpressed in human MLL rearrangement leukemias, are also consistently overexpressed in mouse MLL rearrangement leukemia cells. Nineteen possible targets of these miRNAs were identified, and two of them (i.e., APP and RASSF2) were confirmed further by luciferase reporter and mutagenesis assays. The identification and validation of consistent changes of gene expression in human and murine MLL rearrangement leukemias provide important insights into the genetic base for MLL-associated leukemogenesis.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.forename: Roger T
authors.initials: RT
authors.lastname: Luo
authors.forename: Shuangli
authors.initials: S
authors.lastname: Mi
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Jingyue
authors.initials: J
authors.lastname: Bao
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.forename: Nimanthi
authors.initials: N
authors.lastname: Jayathilaka
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Catherine
authors.initials: C
authors.lastname: Lavau
authors.forename: Yanming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Charles
authors.initials: C
authors.lastname: Tseng
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.forename: San Ming
authors.initials: SM
authors.lastname: Wang
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thirman
mesh_terms: D000818:Animals; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D023461:Myeloid Progenitor Cells / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods
chemical_list: C497422:KMT2A protein, human; C472772:MLL-ELL fusion protein, human; C425207:MLL-ENL oncoprotein, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse