Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias.
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.
Li
Zejuan
Z
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Luo
Roger T
RT
Mi
Shuangli
S
Sun
Miao
M
Chen
Ping
P
Bao
Jingyue
J
Neilly
Mary Beth
MB
Jayathilaka
Nimanthi
N
Johnson
Deborah S
DS
Wang
Lili
L
Lavau
Catherine
C
Zhang
Yanming
Y
Tseng
Charles
C
Zhang
Xiuqing
X
Wang
Jian
J
Yu
Jun
J
Yang
Huanming
H
Wang
San Ming
SM
Rowley
Janet D
JD
Chen
Jianjun
J
Thirman
Michael J
MJ
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
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