Suppression of Let-7b MicroRNA and Enhanced Its Target genes in Infant Acute Lymphoblastic Leukemia with MLL Gene Rearrangements.

MicroRNAs (miRs) play an important role in leukemogenesis; specific miRs are underexpressed, whereas others are overexpressed in leukemias. In addition, to regulate the leukemogenesis, each specific miRs repress one or many target genes. These findings indicate that some specific miRs can regulate the leukemogenesis also in infant ALL. Recently, the etiology of infant leukemia has been calrified; in utero exposure to topoisomerase-II inhibitors and other factors may affect MLL gene rearrangements, which lead to induction of leukemogenesis. After birth, specific oncogenes and proliferation or differentiation factors will be disrupted via enhanced HoxA9 by the stimulation of MLL fusion genes. In this study, let-7b miR and its regulator lin28 are suppressed, followed by the enhanced expression of HoxA9 and HMGA2 oncogene in MLL-rearranged infant ALL.

Leukemic cells from ALL infants and ALL cell lines with and without MLL gene rearrangements were used. In microarray analysis, miR was extracted and analysis was performed by using the mirVana^TM miRNA Bioarray V2 system. Quadruplicated data were averaged, and all miRs with >2-fold different expression was considered as significant in this study. Then, TaqMan real-time PCR method was used to quantify the expression of each miR. The relative expression of each gene was calculated by setting the control normal B lymphocytes. Finally, the transfection of MLL fusion genes to HEK293 cells was performed to induce let-7b expression in vitro.

By the microarray analysis, 13 miRs showed >2-fold lower expression in MLL-rearranged ALLs than MLL-germline ALLs, including miR-124a, miR-153, and let-7b with >5-fold lower expression. When we focused on let-7b, expressions of let-7b, its associated genes lin28 and Dicer were significantly lower in MLL-rearranged ALLs than MLL-germline ALLs. MLL-rearranged ALLs showed high expression of HoxA9 and HMGA2, possible target genes for let-7b. The in vitro transfection of MLL fusion genes to HEK293 cells also induced the suppression of let-7b.

Our study first demonstrated that the expressions of let-7b is significantly decreased in MLL-rearranged ALL cells. Let-7 family has been reported as tumor-suppressor gene in cancer; the expression level of let-7 family increases during differentiation of cancer cells, while its target genes show a reciprocal expression pattern. However, it remains to be explored whether let-7 might be involved directly or indirectly in the leukemia-related functions.

The interaction between HoxA9 disrupted by MLL fusion and HMGA2 oncogene regulated by specific miRs including let-7 could be involved in the pathogenesis of infant ALL with MLL gene rearrangements. These genes might become a target for therapeutic approach in the future.

No relevant conflicts of interest to declare.