KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation

Youl Nam Lee, Stephanie Brandal, Pierre Noel, Erik Wentzel, Joshua T. Mendell, Michael A. McDevitt, Reuben Kapur, Melody Carter, Dean D. Metcalfe, Clifford M. Takemoto

Research output: Contribution to journalArticle

Abstract

Activating mutations in codon D816 of the tyrosine kinase receptor, KIT, are found in the majority of patients with systemic mastocytosis. We found that the transcription factor, microphthalmia-associated transcription factor (MITF), is highly expressed in bone marrow biopsies from 9 of 10 patients with systemic mastocytosis and activating c-KIT mutations. In primary and transformed mast cells, we show that KIT signaling markedly up-regulates MITF protein. We demonstrate that MITF is required for the proliferative phenotype by inhibiting colony-forming units with sh-RNA knockdown of MITF. Furthermore, constitutively active KIT does not restore growth of primary MITF-deficient mast cells. MITF mRNA levels do not change significantly with KIT signaling, suggesting posttranscriptional regulation. An array screen from mast cells identified candidate miRNAs regulated by KIT signaling. We found that miR-539 and miR-381 are downregulated by KIT signaling and they repressed MITF expression through conserved miRNA binding sites in the MITF 3′-untranslated region. Forced expression of these miRNAs suppressed MITF protein and inhibited colony-forming capacity of mastocytosis cell lines. This work demonstrates a novel regulatory pathway between 2 critical mast cell factors, KIT and MITF, mediated by miRNAs; dysregulation of this pathway may contribute to abnormal mast cell proliferation and malignant mast cell diseases.

Original languageEnglish (US)
Pages (from-to)3629-3640
Number of pages12
JournalBlood
Volume117
Issue number13
DOIs
StatePublished - Mar 31 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Lee, Y. N., Brandal, S., Noel, P., Wentzel, E., Mendell, J. T., McDevitt, M. A., Kapur, R., Carter, M., Metcalfe, D. D., & Takemoto, C. M. (2011). KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation. Blood, 117(13), 3629-3640. https://doi.org/10.1182/blood-2010-07-293548