Expression of miR-196b is not exclusively MLL-driven but is especially linked to activation of HOXA genes in pediatric acute lymphoblastic leukemia

• Published in: Haematologica (Roma) 2010-10, Vol.95 (10), p.1675-1682
• Main Authors: SCHOTTE, Diana, LANGE-TURENHOUT, Ellen A. M, STUMPEL, Dominique J. P. M, STAM, Ronald W, BUIJS-GLADDINES, Jessica G. C. A. M, MEIJERINK, Jules P. P, PIETERS, Rob, DEN BOER, Monique L
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Child; Epigenomics; Gene Expression Regulation, Leukemic; Gene Rearrangement; Hematologic and hematopoietic diseases; Homeodomain Proteins - genetics; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; MicroRNAs - biosynthesis; MicroRNAs - genetics; Myeloid-Lymphoid Leukemia Protein - genetics; Original; Precursor Cell Lymphoblastic Leukemia-Lymphoma - etiology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2010.023481

Deregulation of microRNA may contribute to hematopoietic malignancies. MicroRNA-196b (miR-196b) is highly expressed in MLL-rearranged leukemia and has been shown to be activated by MLL and MLL-fusion genes. In order to determine whether high expression of miR-196b is restricted to MLL-rearranged leukemia, we used quantitative stem-loop reverse transcriptase polymerase chain reaction to measure the expression of this microRNA in 72 selected cases of pediatric acute lymphoblastic leukemia i.e. MLL-rearranged and non-MLL-rearranged precursor B-cell and T-cell acute lymphoblastic leukemias. We also determined the expression of HOXA-genes flanking miR-196 by microarray and real-time quantitative polymerase chain reaction. Furthermore, we used CpG island-arrays to explore the DNA methylation status of miR-196b and HOXA. We demonstrated that high expression of miR-196b is not unique to MLL-rearranged acute lymphoblastic leukemia but also occurs in patients with T-cell acute lymphoblastic leukemia patients carrying CALM-AF10, SET-NUP214 and inversion of chromosome 7. Like MLL-rearrangements, these abnormalities have been functionally linked with up-regulation of HOXA. In correspondence, miR-196b expression in these patients correlated strongly with the levels of HOXA family genes (Spearman's correlation coefficient ≥ 0.7; P≤0.005). Since miR-196b is encoded on the HOXA cluster, these data suggest co-activation of miR-196b and HOXA genes in acute lymphoblastic leukemia. Up-regulation of miR-196b coincides with reduced DNA methylation at CpG islands in the promoter regions of miR-196b and the entire HOXA cluster in MLL-rearranged cases compared to in cases of non-MLL precursor B-cell acute lymphoblastic leukemia and normal bone marrow (P