Abstract
The MYB oncogene is a leucine zipper transcription factor essential for normal and malignant hematopoiesis. In T-cell acute lymphoblastic leukemia (T-ALL), elevated MYB levels can arise directly through T-cell receptor-mediated MYB translocations, genomic MYB duplications or enhanced TAL1 complex binding at the MYB locus or indirectly through the TAL1/miR-223/FBXW7 regulatory axis. In this study, we used an unbiased MYB 3'untranslated region-microRNA (miRNA) library screen and identified 33 putative MYB-targeting miRNAs. Subsequently, transcriptome data from two independent T-ALL cohorts and different subsets of normal T-cells were used to select miRNAs with relevance in the context of normal and malignant T-cell transformation. Hereby, miR-193b-3p was identified as a novel bona fide tumor-suppressor miRNA that targets MYB during malignant T-cell transformation thereby offering an entry point for efficient MYB targeting-oriented therapies for human T-ALL.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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F-Box Proteins / genetics
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F-Box Proteins / metabolism
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F-Box-WD Repeat-Containing Protein 7
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic*
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Genomic Library
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Humans
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Mice
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Primary Cell Culture
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-myb / genetics*
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Proto-Oncogene Proteins c-myb / metabolism
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Signal Transduction
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T-Cell Acute Lymphocytic Leukemia Protein 1
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T-Lymphocytes / metabolism*
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T-Lymphocytes / pathology
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Transcriptome
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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3' Untranslated Regions
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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FBXW7 protein, human
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MIRN193 microRNA, human
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MIRN223 microRNA, human
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MicroRNAs
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myb
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T-Cell Acute Lymphocytic Leukemia Protein 1
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TAL1 protein, human
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Ubiquitin-Protein Ligases