Consistent Deregulation of Gene Expression between Human and Murine MLL Rearrangement Leukemias

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 3; pp. 1109 - 1116
• Main Authors: ZEJUAN LI, LUO, Roger T, LAVAU, Catherine, YANMING ZHANG, TSENG, Charles, XIUQING ZHANG, JIAN WANG, JUN YU, HUANMING YANG, SAN MING WANG, ROWLEY, Janet D, JIANJUN CHEN, SHUANGLI MI, THIRMAN, Michael J, MIAO SUN, PING CHEN, JINGYUE BAO, BETH NEILLY, Mary, JAYATHILAKA, Nimanthi, JOHNSON, Deborah S, LILI WANG
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2009
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; DNA Methylation; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene Rearrangement; Hematologic and hematopoietic diseases; Histone-Lysine N-Methyltransferase; Humans; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; MicroRNAs - genetics; Myeloid Progenitor Cells - pathology; Myeloid-Lymphoid Leukemia Protein - biosynthesis; Myeloid-Lymphoid Leukemia Protein - genetics; Oncogene Proteins, Fusion - biosynthesis; Oncogene Proteins, Fusion - genetics; Pharmacology. Drug treatments; Polymerase Chain Reaction - methods; Tumors; Human; Leukemia; Rodentia; Malignant hemopathy; Gene expression; Vertebrata; Mammalia; Mouse; Animal; C-Onc gene; Gene rearrangement; Protooncogene; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3381

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.