title: Transcriptional regulation of SPROUTY2 by MYB influences myeloid cell proliferation and stem cell properties by enhancing responsiveness to IL-3.
abstract: Myeloproliferative neoplasms (MPN), which overproduce blood cells in the bone marrow, have recently been linked with a genetically determined decrease in expression of the MYB transcription factor. Here, we use a mouse MYB knockdown model with an MPN-like phenotype to show how lower levels of MYB lead to stem cell characteristics in myeloid progenitors. The altered progenitor properties feature elevated cytokine responsiveness, especially to interleukin-3, which results from increased receptor expression and increased MAPK activity leading to enhanced phosphorylation of a key regulator of protein synthesis, ribosomal protein S6. MYB acts on MAPK signaling by directly regulating transcription of the gene encoding the negative modulator SPRY2. This mechanistic insight points to pathways that might be targeted therapeutically in MPN.
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: M
authors.initials: M
authors.lastname: Clarke
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: G
authors.initials: G
authors.lastname: Volpe
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: L
authors.initials: L
authors.lastname: Sheriff
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: D
authors.initials: D
authors.lastname: Walton
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: C
authors.initials: C
authors.lastname: Ward
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: W
authors.initials: W
authors.lastname: Wei
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Dumon
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: P
authors.initials: P
authors.lastname: García
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Frampton
mesh_terms: D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D049109:Cell Proliferation; D005312:Fetal Blood / Q000166:cytology; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D007377:Interleukin-3 / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008958:Models, Molecular; D022423:Myeloid Cells / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D016185:Receptors, Interleukin-3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020598:Proto-Oncogene Proteins c-myb; D016185:Receptors, Interleukin-3; C485561:SPRY2 protein, human