Abstract
The promyelocytic leukemia zinc-finger protein (PLZF) is a transcription factor and c-kit is a receptor tyrosine kinase associated with human disease, particularly in hematopoietic cells. MicroRNAs (miRs) are post-transcriptional regulators of gene expression, and c-kit has been described as a target of miRs-221 and -222 in erythropoiesis. In the present study, we identified c-kit as a target of PLZF in normal and leukemic cells. Particularly, in erythropoietic (E) culture of CD34+ progenitors, PLZF is downregulated, whereas c-kit expression at both the mRNA and protein levels inversely increases during the first days of E differentiation. In functional experiments, PLZF transfection induces c-kit downregulation, inhibits E proliferation and delays differentiation, whereas PLZF knockdown induces opposite effects, independently of miRs-221 and -222 expression. The inverse correlation between PLZF and c-kit expression was found in normal CD34+38+/− hematopoietic progenitor/stem cells and in acute myeloid leukemias of M0/M1 French–American–British subtypes, suggesting that the control of PLZF on c-kit expression may be crucial at the level of the stem cell/progenitor compartment. Altogether, our data indicate a new mechanism of regulation of c-kit expression that involves a transcriptional control by PLZF in CD34+ cells and early erythropoiesis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ball H, Melnick A, Shaknovich R, Kohanski R, Licht JD . (1999). The promyelocytic leukemia zinc finger (PLZF) protein binds DNA in a high molecular weight complex associated with cdc2 kinase. Nucleic Acids Res 27: 4106–4113.
Bene MC, Bernier M, Casasnovas RO, Castoldi G, Knapp W, Lanza F et al. (1998). The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. Blood 92: 596–599.
Broudy VC . (1997). Stem cell factor and hematopoiesis. Blood 90: 1345–1364.
Buaas FW, Kirsh AL, Sharma M, McLean DJ, Morris JL, Griswold MD et al. (2004). Plzf is required in adult male germ cells for stem cell self-renewal. Nat Genet 36: 647–652.
Cascavilla N, Musto P, D'Arena G, Melillo L, Carella AM, Petrilli MP et al. (1998). CD117 (c-kit) is a restricted antigen of acute myeloid leukemia and characterizes early differentiative levels of M5 FAB subtype. Haematologica 83: 392–397.
Costoya JA, Hobbs RM, Barna M, Cattoretti G, Manova K, Sukhwani M et al. (2004). Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36: 653–659.
Dang DT, Pevsner J, Yang VW . (2000). The biology of the mammalian Krüppel-like family of transcription factors. Int J Biochem Cell Biol 32: 1103–1121.
Edling CE, Hallberg B . (2007). c-Kit—a hematopoietic cell essential receptor tyrosine kinase. Int J Biochem Cell Biol 9: 1995–1998.
Felicetti F, Bottero L, Mattia G, Labbaye C, Alvino E, Peschle C et al. (2004). Role of PLZF in melanoma progression. Oncogene 23: 4567–4576.
Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F et al. (2005). MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA 102: 18081–18086.
Filipponi D, Hobbs RM, Ottolenghi S, Rossi P, Jannini EA, Pandolfi PP et al. (2007). Repression of kit expression by Plzf in germ cells. Mol Cell Biol 27: 6770–6781.
Gabbianelli M, Testa U, Massa A, Pelosi E, Sposi NM, Riccioni R et al. (2000). Hemoglobin switching in unicellular erythroid culture of sibling erythroid burst-forming units: kit ligand induces a dose-dependent fetal hemoglobin reactivation potentiated by sodium butyrate. Blood 95: 3555–3561.
Gazitt Y . (2004). Homing and mobilization of hematopoietic stem cells and hematopoietic cancer cells are mirror image processes, utilizing similar signalling pathway and occurring concurrently: circulation cancer cells constitute an ideal target for concurrent treatment with chemotherapy and antilineage-specific antibodies. Leukemia 18: 1–10.
He L, Hannon GJ . (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5: 522–531.
Isken F, Steffen B, Merk S, Dugas M, Markus B, Tidow N et al. (2008). Identification of acute myeloid leukaemia associated microRNA expression patterns. Br J Haematol 140: 153–161.
Ivins S, Pemberton K, Guidez F, Howell L, Krumlauf R, Zelent A . (2003). Regulation of hoxb2 by APL-associated PLZF protein. Oncogene 22: 3685–3697.
Jing H, Vakoc CR, Ying L, Mandat S, Wang H, Zheng X et al. (2008). Exchange of GATA factors mediates transitions in looped chromatin organization at a developmentally regulated gene locus. Mol Cell 29: 232–242.
Kelly KF, Daniel JM . (2006). POZ for effect-POZ-ZF transcription factors in cancer and development. Trends Cell Biol 16: 578–587.
Labbaye C, Quaranta MT, Pagliuca A, Militi S, Licht JD, Testa U et al. (2002). PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein. Oncogene 21: 6669–6679.
Labbaye C, Spinello I, Quaranta MT, Pelosi E, Pasquini L, Petrucci E et al. (2008). A pathway comprising PLZF microRNA 146a and its target CXCR4 controls megakaryopoiesis. Nat Cell Biol 10: 788–801.
Lennartson J, Jelacic T, Linnekin D, Shivakrupa R . (2005). Normal and oncogenic forms of the receptor tyrosine kinase kit. Stem Cells 23: 16–43.
Majeti R, Park CY, Weissman IL . (2007). Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell 1: 635–645.
Melnick A, Licht JD . (1999). Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215.
Muta K, Krantz SB, Bondurant MC, Dai CH . (1995). Stem cell factor retards differentiation of normal human erythroid progenitor cells while stimulating proliferation. Blood 86: 572–580.
Munugalavadla V, Kapur R . (2005). Role of c-kit and erythropoietin receptor in erythropoiesis. Crit Rev Oncol Hematol 54: 63–75.
Parrado A, Noguera ME, Delmer A, McKenna S, Davies J, Le Gall I et al. (2000). Deregulated expression of promyelocytic leukemia zinc finger protein in B-cell chronic lymphocytic leukemias does not affect cyclin A expression. Hematol J 1: 15–27.
Patnaik MM, Tefferi A, Pardanani A . (2007). Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders. Curr Cancer Drug Targets 7: 492–503.
Quaranta MT, Spinello I, Testa U, Mariani G, Diverio D, Foà R et al. (2006). PLZF-mediated control on VLA-4 expression in normal and leukemic myeloid cells. Oncogene 25: 399–408.
Scolnik MP, Morilla R, de Bracco MM, Catovsky D, Matutes E . (2002). CD34 and CD117 are overexpressed in AML and may be valuable to detect minimal residual disease. Leuk Res 26: 615–619.
Sperling C, Schwartz S, Büchner T, Thiel E, Ludwig WD . (1997). Expression of the stem cell factor receptor C-KIT (CD117) in acute leukemias. Haematologica 82: 617–621.
Tsuzuki S, Enver T . (2002). Interactions of GATA-2 with the promyelocytic leukemia zinc finger (PLZF) protein, its homologue FAZF, and the t(11;17)-generated PLZF-retinoic acid receptor alpha oncoprotein. Blood 99: 3404–3410.
Wessely O, Mellitzer G, von Lindern M, Levitzki A, Gazit A, Ischenko I et al. (1997). Distinct roles of the receptor tyrosine kinases c-ErbB and c-Kit in regulating the balance between erythroid cell proliferation and differentiation. Cell Growth Differ 8: 481–493.
Yamamoto K, Tojo A, Aoki N, Shibuya M . (1993). Characterization of the promoter region of the human c-kit proto-oncogene. Jpn J Cancer Res 84: 1136–1144.
Acknowledgements
We thank Dr F Spadaro, from the Department of Cell Biology and Neuroscience, for her help with confocal microscopy and G Loreto for graphics. This work was supported by institutional grants from the Italian Ministry of Health to UT and CL, from Associazione Italiana per la Ricerca sul Cancro (AIRC) to RF, and from ‘Fondazione Roma’, Rome, Italy to UT.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Spinello, I., Quaranta, M., Pasquini, L. et al. PLZF-mediated control on c-kit expression in CD34+ cells and early erythropoiesis. Oncogene 28, 2276–2288 (2009). https://doi.org/10.1038/onc.2009.87
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2009.87
Keywords
This article is cited by
-
Renin–angiotensin system in ureteric bud branching morphogenesis: implications for kidney disease
Pediatric Nephrology (2014)
-
Expression of the promyelocytic leukemia zinc-finger in T-lymphoblastic lymphoma and leukemia has strong implications for their cellular origin and greater association with initial bone marrow involvement
Modern Pathology (2012)
-
MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias
Blood Cancer Journal (2011)