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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements

Abstract

MicroRNAs (miRNAs) regulate cell proliferation and differentiation by controlling the expression of proteins involved in many signaling pathways. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenicity and a poor prognosis in several types of cancers. The miRNA let-7b is one of the severely downregulated miRNAs in mixed-lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL) patients. In vitro transfection of leukemogenic MLL fusion genes into human embryonic kidney-293 cells suppressed let-7b expression. In leukemic cells with an MLL fusion gene, the regulatory region for let-7b expression was hypermethylated, and its expression was partially recovered after culturing the cells with the demethylating agent 5-azacitidine. These results suggest that loss of let-7b expression may be one of the consequences of oncogenic MLL fusion proteins, and contributes to leukemogenesis possibly through the upregulation of let-7b-regulated target genes with leukemogenic potential in hematopoietic cells. The enforced expression of let-7b in ALL cell lines with an MLL fusion gene inhibited their growth, indicating the possible use of let-7b as a new therapeutic tool for refractory infant ALL with an MLL fusion gene.

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Acknowledgements

We thank Ms Risa Sogabe and Ms Chihiro Tanaka for technical assistance, and Dr Yujiro Sadakane for technical assistance in microarray analysis. We thank Dr Daisuke Tomizawa and Professor Shuki Mizutani of Tokyo Medical and Dental University for providing some of the infant leukemic samples. We also thank Dr Naoto Fujita, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital for the TEL–AML1-positive leukemic samples. We thank all members of the Committee of the Japan Infant Leukemia Study Group for their contributions to sample collection. The REH cell line was a kind gift from Dr Yoshinobu Matsuo of Fujisaki Cell Center, Hayashibara Biochemical Laboratories. This study was supported by the Japan Children’s Cancer Association, a Grant-in-Aid for Scientific Research and a Grant-in-Aid for Cancer Research from the Ministry of Health and Labor of Japan.

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Correspondence to M Eguchi.

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Nishi, M., Eguchi-Ishimae, M., Wu, Z. et al. Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements. Leukemia 27, 389–397 (2013). https://doi.org/10.1038/leu.2012.242

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