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 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.

Aberrant overexpression and function of the miR-17-92 cluster in MLL -rearranged acute leukemia

“…Experimental data shows that MLL fusions inhibit hematopoietic differentiation in serial replating assays, a critical surrogate parameter for transformation activity (26,27). Although MLL-associated leukemias have been intensively studied, how miRNAs contribute to their development and how they can contribute or trigger the clonogenic capacity of MLLfusion dependent clones are largely unknown.We previously reported that the individual miRNAs of the miR-17-92 cluster were overexpressed in the majority of MLL-rearranged AML (16,28). In the present study, we demonstrate that the miR-17-92 cluster is highly expressed not only in MLL-associated AML, but also in MLL-associated ALL.…”

“…We previously reported that the individual miRNAs of the miR-17-92 cluster were overexpressed in the majority of MLL-rearranged AML (16,28). In the present study, we demonstrate that the miR-17-92 cluster is highly expressed not only in MLL-associated AML, but also in MLL-associated ALL.…”

MicroRNAs in acute leukemia: from biological players to clinical contributors

“…34 These potential target genes were all downregulated in MLL-rearranged ALL. 32,34,61 Two genes, that is, APP and RASSF2 were confirmed targets for miR-17-92 as shown by a luciferase 3 0 UTR-binding assay 34 and the expression of one gene (that is, TNFRSF21) inversely correlated with the expression of the miR-17-92 cluster. 32 The miR-17-92 cluster also has a oncogenic role in T-ALL.…”

“…20,21,[32][33][34]61 Together with the fact that this polycistronic cluster cooperated with c-Myc to accelerate B-cell lymphoma formation in vivo 62 suggests that miR-17-92 acts as an oncogene in lymphoid tissue. Induced expression of the miRNA cluster enhanced the colony-forming capacity of mouse bone marrow progenitors especially when MLL fusion genes were co-expressed.…”

“…High expression of another set of miRNAs including miR-382 was unique for t(15;17)/PML-RARa-positive AML. 18,20 MLL-rearranged AML cases, the oncogenic miR-17-92 cluster was upregulated 21,34,32 whereas the tumor-suppressor miR-29 was downregulated (Table 2). 19,23 MiRNA expression levels are also associated with molecular subtypes of AML, the mutational status and associated gene expression pattern in AML (Table 2).…”