Genes Similarly Abnormally Expressed in Both Human and Murine MLL-Associated Leukemia.

Abstract

Although more than 50 different loci translocate to the MLL gene at chromosome band 11q23, resulting in either acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), no unifying property is shared by all partner genes. The translocations result in a functional fusion of the N-terminal part of MLL gene and the C-terminal part of each partner gene, presumably leading to changes in the expression of the normal target genes, most of which have not been identified. Although genetically engineered mouse leukemia models have been widely used, few systematic studies have evaluated whether such models are valid equivalents of human leukemia. We used serial analysis of gene expression (SAGE) to obtain genome-wide gene expression profiles in normal myeloid progenitor cells from human CD15+ and mouse Gr-1+ cells. We also analyzed four patient samples (two with each fusion) and two retrovirally-induced mouse leukemias containing either MLL-ELL [t(11;19)(q23;p13.1)] or MLL-ENL [t(11;19)(q23;p13.3)] fusions, and a cell line from a leukemia mouse transduced with an MLL-ELL fusion. MLL-ELL and MLL-ENL fusions are frequently involved in human AML, while MLL-ENL is also seen in human ALL. 484,303 SAGE tags were identified from the nine samples (40,000 to 100,000 tags per sample), yielding 103,899 unique SAGE tags in the human and 60,993 in the mouse samples. Analysis of the SAGE data identified 43 candidate genes that appear to be abnormally expressed in both human and mouse myeloid leukemia progenitor cells with either MLL-ELL or MLL-ENL fusions (9 up-regulated and 34 down-regulated; Table 1). Increasing evidence suggests that endogenous antisense RNAs may play critical roles in gene regulation and cancer. Natural antisense RNAs include cis-encoded antisense RNAs transcribed from the opposite strand of the same genomic locus as the sense target genes, and trans-encoded antisense RNAs such as microRNAs (miRNAs) transcribed from a genomic locus different from the sense target genes. 26 of the 43 candidate genes have antisense partners (with a total of 7 cis-encoded antisense RNAs and 36 trans-encoded miRNAs) and thereby might be regulated by endogenous antisense RNAs. We are currently validating the expression pattern of the 43 candidate genes in at least 30 different human and mouse leukemia and normal control samples with quantitative RT-PCR, and measuring the level of expression of all known miRNAs via microarray in these samples. Our studies on the abnormally expressed genes and their potential antisense partners will provide important insights into the complex functional pathways related to MLL rearrangements in the development of acute leukemia, which may lead to more effective therapy for these leukemias.Table 1Genes deregulated in both human and mouse leukemiasaTotal numberUp-regulated genesDown-regulated genesGenes with antisense partner(s)In MLL-ELL fusions2112012In MLL-ENL fusions3382521In both types of fusions110117Total unique genes4393426aThe genes have at least 3 fold difference in expression with a significance P < 0.05 between each leukemia sample and the normal control sample.