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Biological Sciences Department Faculty
Fan Dong, M.D., Ph.D.
Office: WO 3257B
The primary focus of my lab is to address the molecular mechanism by which granulocyte colony-stimulating factor (G-CSF) regulates the development of myeloid cells. G-CSF is the most important regulator of granulopoiesis, a process of producing mature granulocytes in the bone marrow. G-CSF exerts its biological activities by binding to the G-CSF receptor, which is a member of the cytokine receptor superfamily. Specifically, we are interested in identifying the signaling pathways that are activated by G-CSF and addressing the roles of these pathways in normal granulopoiesis and, when deregulated, in leukemogenesis.
Selected current projects
CSF3R mutations in severe congenital neutropenia (SCN)
SCN is a group of heterogeneous disorders characterized by severe absolute neutropenia occurring in early life and a maturation arrest of bone marrow myeloid cells at the promyelocyte stage. Inherited or spontaneous point mutations in ELA2, which encodes neutrophil elastase (NE), have been detected in approximately 60 to 80 % of patients with SCN. SCN patients are at increased risk of developing acute myeloid leukemia (AML). Significantly, progression from SCN to AML is associated with acquisition of somatic CSF3R mutations in approximately 80% of the patients, causing carboxy terminal truncation of the G-CSF receptor. We have observed that the carboxy terminal region of the G-CSF receptor is required for induction of NE expression by G-CSF. We are now trying to determine the G-CSF-activated signaling pathways leading to induction of NE expression. As NE is an important marker of granulocytic differentiation, elucidation of the signaling pathways has important implications for understanding how G-CSF regulates granulopoiesis.
Gfi-1 in the regulation of hematopoiesis
Gfi-1 encodes a nuclear zinc-finger (ZF) transcriptional repressor that is expressed primarily in the hematopoietic system. Gfi-1 promotes the proliferation and survival of T and B cells, and plays a critical role in granulopoiesis. Gfi-1 has also been shown to function as an oncoprotein in lymphomagenesis. We recently showed that Gfi-1 expression is upregulated by G-CSF and the carboxy terminus of the G-CSF receptor is required for Gfi-1 upregulation. Interestingly, Gfi-1 interacts with Miz-1, a POZ domain ZF transcription factor, and represses CDK inhibitors p21Cip and p15INK4B through Miz-1 interaction. Our more recent data further implicate Gfi-1 in the regulation of cellular responses to TGFb and DNA damage. We are currently investigating the mechanism of Gfi-1 actions and the significance of Gfi-1/Miz-1 interaction in normal hematopoiesis and lymphomagenesis.
Du P, Tang F, Qiu Y, Dong F. GFI1 is repressed by p53 and inhibits DNA damage-induced apoptosis. PLoS One. 2013 Sep 4;8(9):e73542. doi: 10.1371/journal.pone.0073542. eCollection 2013.
Liu Q, Dong F. Gfi-1 inhibits the expression of eosinophil major basic protein (MBP) during G-CSF-induced neutrophilic differentiation. Int J Hematol. 2012 Jun;95(6):640-7. doi: 10.1007/s12185-012-1078-x. Epub 2012 May 3.
Liu Q, Basu S, Qiu Y and Dong F. Miz-1 is involved in Gfi-1-mediated transcriptional repression of CDKN1A. J Biol Chem. Submitted.
Basu S, Liu Q, Qiu Y, Dong F. (2009) Gfi-1 represses CDKN2B encoding p15INK4B through interaction with Miz-1. Proc Natl Acad Sci U S A.106:1433.
Zhuang D, Qiu Y, Kogan SC, and Dong F. (2006) Increased CCAAT enhancer-binding protein epsilon (C/EBPepsilon) expression and premature apoptosis in myeloid cells expressing Gfi-1 N382S mutant associated with severe congenital neutropenia. J Biol Chem 281:10745.
Liu H, Qiu Y, Xiao L, and Dong F. (2006) Involvement of protein kinase Cepsilon in the negative regulation of Akt activation stimulated by granulocyte colony-stimulating factor. J Immunol 176:2407.
Zhuang D, Qiu Y, Haque SJ and Dong F. (2005). Tyrosine 729 of the G-CSF receptor controls the duration of Stat5 activation: involvement of SOCS3 and SOCS1. J Leukoc Biol 78:1008.
Qiu Y, Zhuang D, Macrae A, Dong F. (2005) The G-CSF receptor carboxyl terminus, truncated in AML/SCN, is required for induction of a Stat5 protease activity. Leuk Res 29:1153.
Shi T, Dong F, Liou LS, Duan ZH, Novick AA and DiDonato JA. (2004) Differential protein expression profiling and gene expression in renal cell carcinoma. Mol Carcinog 40:47.
Dong F, Qiu Y, Yi T, Touw IP and Larner AC. (2001) The carboxy terminus of the granulocyte colony-stimulating factor receptor, truncated in patients with severe congenital neutropenia/acute myeloid leukemia, is required for SH2-containing phosphatase-1 suppression of Stat activation. J Immunol 167: 6447.
Dong F, Gutkind JS and Larner AC. (2001) Granulocyte colony-stimulating factor induces Erk5 activation, which is differentially regulated by protein-tyrosine kinases and protein kinase C. Regulation of cell proliferation and survival. J Biol Chem 276:10811.
Dong F, Larner AC. (2000) Activation of Akt kinase by granulocyte colony-stimulating factor (G-CSF): evidence for the role of a tyrosine kinase activity distinct from the Janus kinase(s). Blood 95:1656.
Grimley PM, Dong F, Rui H. (1999) Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation. Cytokine Growth Factor Rev 10:131.
Dong F, Liu, X, de Koning JP, Touw, IP, Hennighausen L, Larner A, Grimley P. (1998) Stimulation of Stat5 by Granulocyte Colony-Stimulating Factor (G-CSF) is Modulated by Two Distinct Cytoplasmic Regions of the G-CSF Receptor. J Immunol 161:6503.
Rui H, Xu J, Mehta S, Fang H, Williams J, Dong F, Grimley PM. (1998) Activation of the Jak2-Stat5 signaling pathway in Nb2 lymphoma cells by an anti-apoptotic agent, aurintricarboxylic acid. J Biol Chem 273:28.
Grimley PM, Fang H, Rui H, Petricoin EF 3rd, Ray S, Dong F, Fields KH, Hu R, Zoon KC, Audet S, Beeler J. (1998) Prolonged STAT1 activation related to the growth arrest of malignant lymphoma cells by interferon-alpha. Blood 91:3017.
Stancato LF, Sakatsume M, David M, Dent P, Dong F, Petricoin EF, Krolewski JJ, Silvennoinen O, Saharinen P, Pierce J, Marshall CJ, Sturgill T, Finbloom D, and Larner AC. (1997) Beta interferon and oncostadin M activate Raf-1 and mitogen-activated protein kinase through a JAK-1-dependent pathway. Mol Cell Biol 17:3833.
Dong F, Dale DC, Bonnila MA, Freedman M, Fasth A, Neijens HJ, Palmblad J, Briars GL, Calsson G, Veerman AJP, Welte K, Lowenberg B, Touw IP. (1997) Mutations in the Granulocyte-Colony Stimulating Factor Receptor Gene in Patients with Severe Congenital Neutropenia. Leukemia 11:120.
Touw IP, Dong F. (1996) Responses of leukemia cells to hematopoietic growth factors: Involvement of autocrine growth mechanisms, cytogenetic abnormalies, and defective maturation signaling. In: Blood Cell Biochemistgry, Vol. 7: Hematopoietic Cell Growth Factors (ed. A Whetton and J Gordon), Plenum, New York, London, Washington D.C., Boston, Moscow, pp303.
Touw IP and Dong F. (1996) Severe Congenital Neutropenia Terminating in Acute Leukemia: Disease Progression Associated with Mutations in the Granulocyte-Colony Stimulating Factor Receptor Gene. Leuk Res 20:629.
Touw IP and Dong F. (1996) Hematopoietic growth factors in leukemia. Path Res Pract 192:734.
Barge RMY, de Koning JP, Pouwels K, Dong F, Lowenberg B, Touw IP. (1996) Tryptophan 650 of Human Granulocyte Colony-Stimulating Factor (G-CSF) Receptor, Implicated in the Activation of JAK2, Is also Required for G-CSF-mediated Activation of Signaling Complexes of the p21ras Route. Blood 87:2148.
de Koning JP, Dong F (Co-first author), Smith L, Schelen AM, Barge RM.Y, van der Plas DC, Hoefsloot LH, Lowenberg B, Touw IP. (1996) The Membrane-Distal Cytoplasmic Region of Human Granulocyte Colony-Stimulating Factor Receptor Is Required for STAT3 but not STAT1 Homodimer Formation. Blood 87:1335.
de Koning JP, Schelen AM, Dong F, van Buitenen C, Burgering BMT, Bos JL, Lowenberg B, Touw IP. (1996) Specific Involvement of Tyrosine 764 of Human Granulocyte Colony-Stimulating Factor Receptor in Signal Transduction Mediated by p145/GRB2 or p90/GRB2 Complexes". Blood 87:132.
Dong F, Pouwls K, Hoefsloot LH, Rozemuller H, Lowenberg B, Touw IP. (1996) The C-terminal Cytoplasmic Region of the Granulocyte Colony-Stimulating Factor Receptor Mediates Apoptosis in Maturation-Incompetent Murine Myeloid Cells". Exp Hematol 24:214.
Budel LM, Dong F, Lowenberg B, Touw IP. (1995) Hematopoietic Growth Factor Receptor: Structure Variations and Alternatives of Receptor Complex Formation in Normal Hematopoiesis and in Hematopoitic Disorders. Leukemia 9:553.
Dong F, Brynes RK, Tidow N, Welte K, Lowenberg B, Touw IP. (1995) Mutations in the Gene for the Granulocyte Colony-Stimulating Factor Receptor in Patients with Acute Myeloid Leukemia Preceded by Severe Congenital Neutropenia". N Engl J Med 333:487.
Dong F, van Paassen M, van Buitenen C, Hoofsloot LH, Lowenberg B, Touw IP. (1995) A Point mutation in the Granulocyte Colony-Stimulating Factor Receptor (G-CSF-R) Gene in a Case of Acute Myeloid Leukemia Results in the Overexpression of a Novel G-CSF-R Isoform. Blood 85:902.
Dong F, Hoefsloot LH, Schelen AM, Broeders LCAM, Meijer Y, Veerman AJP, Touw IP, Lowenberg B. (1994) Identification of a Nonsense Mutation in the Granulocyte-Colony Stimulating Factor Receptor in Severe Congenital Neutropenia. Proc Natl Acad Sci USA 91:4480.
Dong F, van Buitenen C, Pouwles K, Hoefsloot LH, Lowenberg B, Touw IP. (1993) Distinct Cytoplasmic Regions of the Human Granulocyte Colony-Stimulating Factor Receptor Involved in Induction of Proliferation and Maturation. Mol Cell Biol 13:7774.