The cloning and characterization of leukemia oncoproteins over the last 25 years has resulted in a greater understanding of the central role of transcription factors in hematopoiesis and leukemogenesis. Human acute myeloid leukemias are characterized by the presence of chromosomal translocations, which, result in the fusion of coding sequences from one gene to coding sequences of transcription factors. Overexpression of these fusion transcription factors often inhibits myeloid differentiation and such fusion transcription factors may play an important role in the development of the leukemic phenotype. Though much is known about the expression of human transcription-factor oncoproteins in clinical disease, their transcriptional targets are not as clear. Growth factor independence-1 (GFI1) is a transcription factor that is essential for normal lymphoid and myeloid development. GFI1 was originally identified as a frequent target of Moloney murine leukemia virus insertion in rat and mouse genomes. Transgenic expression of GFI1 is oncogenic and potently accelerates leukemogenesis induced by the Moloney murine leukemia virus; confirming the role of GFI1 in Moloney oncogenesis. Mutation of GFl1 leads to a human neutropenia syndrome that predisposes to acute myeloid leukemia. Our preliminary evidence indicates that GFl1 is targeted by a chimeric transcription factor found in human acute myeloid leukemia, and that GFI1 targets key myeloid lineage transcription factors. We hypothesize that GFI1 tethers a multiprotein transcription complex to DNA to control the expression of lineage-specific transcription factors, and that abnormal GFl1 expression predisposes to acute myeloid leukemia. We will molecularly characterize GFI1 target genes in myelopoiesis, and biologically test suggested genetic interactions. Moreover, we will dissect GFl1 as a target of a human chimeric transcription factor oncoprotein, and determine whether loss of GFl1 is predisposing to leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA105152-02
Application #
6913629
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2004-07-01
Project End
2005-09-30
Budget Start
2005-07-01
Budget End
2005-09-30
Support Year
2
Fiscal Year
2005
Total Cost
$10,936
Indirect Cost
Name
University of Louisville
Department
Surgery
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Velu, Chinavenmeni S; Chaubey, Aditya; Phelan, James D et al. (2014) Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. J Clin Invest 124:222-36
Khandanpour, Cyrus; Phelan, James D; Vassen, Lothar et al. (2013) Growth factor independence 1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia. Cancer Cell 23:200-14
Phelan, James D; Saba, Ingrid; Zeng, Hui et al. (2013) Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. PLoS Genet 9:e1003713
Meyer, Sara E; Hasenstein, Jason R; Baktula, Avinash et al. (2010) Kruppel-like factor 5 is not required for K-RasG12D lung tumorigenesis, but represses ABCG2 expression and is associated with better disease-specific survival. Am J Pathol 177:1503-13
Horman, Shane R; Velu, Chinavenmeni S; Chaubey, Aditya et al. (2009) Gfi1 integrates progenitor versus granulocytic transcriptional programming. Blood 113:5466-75
Salipante, Stephen J; Rojas, Meghan E B; Korkmaz, Brice et al. (2009) Contributions to neutropenia from PFAAP5 (N4BP2L2), a novel protein mediating transcriptional repressor cooperation between Gfi1 and neutrophil elastase. Mol Cell Biol 29:4394-405
Popovic, Relja; Riesbeck, Laurie E; Velu, Chinavenmeni S et al. (2009) Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood 113:3314-22
Zarebski, Adrian; Velu, Chinavenmeni S; Baktula, Avinash M et al. (2008) Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1. Immunity 28:370-80
Montoya-Durango, Diego E; Velu, Chinavenmeni S; Kazanjian, Avedis et al. (2008) Ajuba functions as a histone deacetylase-dependent co-repressor for autoregulation of the growth factor-independent-1 transcription factor. J Biol Chem 283:32056-65
Wojciechowski, Sara; Tripathi, Pulak; Bourdeau, Tristan et al. (2007) Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis. J Exp Med 204:1665-75

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