miR-3151 interplays with its host gene BAALC and independently impacts on outcome of patients with cytogenetically normal acute myeloid leukemia

• Main Author: Eisfeld, Ann-Kathrin
• Other Authors: Universitaet Leipzig, Haematologie/Onkologie
• Format: Doctoral Thesis
• Language: English
• Published: Universitätsbibliothek Leipzig 2014
• Subjects: AML; microRNAs; prognosis; miR; ddc:610
• Online Access: http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-142891; http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-142891; http://www.qucosa.de/fileadmin/data/qucosa/documents/14289/Promotion_Eisfeld_for%20library.pdf

High expression levels of the gene BAALC (brain and acute leukemia, cytoplasmic) are associated with poor prognosis in acute myeloid leukemia (AML) patients, but the underlying mechanisms are not yet understood. We evaluated the prognostic significance of expression levels of miR-3151, a newly discovered microRNA embedded in intron 1 of the BAALC gene, in a cohort of 179 older (≥60 years) cytogenetically normal AML (CN-AML) patients, in the context of established molecular markers and especially with regard to the possible interplay with its host gene BAALC. In multivariable analyses, high miR-3151 was associated with shorter disease-free and overall survival (OS), while higher BAALC expression strongly predicted failure of complete remission attainment and OS. Patients exhibiting both high miR-3151 and BAALC expression had worse outcome than patients expressing low levels of either one of the genes or both. Next, gene - and microRNA-expression profiles associated with miR-3151 expression were derived using microarrays, and a pathway analysis of the miR-3151 associated gene signature was performed using Ingenuity software. High miR-3151 expressers showed downregulation of genes involved in transcriptional regulation, post-translational modifications and cell-cycle control. Two genes of the ubiquitination pathway, FBXL20 and USP40, were experimentally validated as direct miR-3151 targets. In summary, we identified high expression levels of the intronic miR-3151 as a novel, independent prognosticator for poor outcome in CN-AML. Interestingly, miR-3151 impacted differently on outcome than its host gene BAALC; and the combination of both markers identified a patient subset with the poorest outcome, suggesting that the microRNA and its host gene contribute to clinical and prognostic features of CN-AML independently and through distinct mechanisms. This is the first example of the interplay of an intronic miR and its host gene in leukemia. Its discovery may have important biologic implications for future targeted treatment strategies.