Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias

Zejuan Li, Roger T. Luo, Shuangli Mi, Miao Sun, Ping Chen, Jingyue Bao, Mary Beth Neilly, Nimanthi Jayathilaka, Deborah S. Johnson, Lili Wang, Catherine Lavau, Yanming Zhang, Charles Tseng, Xiuqing Zhang, Jian Wang, Jun Yu, Huanming Yang, San Ming Wang, Janet D. Rowley, Jianjun ChenMichael J. Thirman

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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 downregulated 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.

Original languageEnglish (US)
Pages (from-to)1109-1116
Number of pages8
JournalCancer Research
Volume69
Issue number3
DOIs
StatePublished - Feb 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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