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Transcriptional Control of Normal Lymphopoiesis and T-cell Neoplasia by Growth Factor Independent 1

Phelan, James D., B.S.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1337351444

Abstract Details

2012, PhD, University of Cincinnati, Medicine: Immunology.
Hematopoietic development is a tightly controlled process in which environmental cues promote or restrict the proliferation and differentiation of bone marrow derived cells. These signals are interpreted and integrated by conserved transcriptional networks that ultimately determine cell fate by activating or repressing lineage-associated genes. Dysregulation of transcription factor function can lead to global defects, cellular reprogramming and transformation. Mutations causing hematologic malignancies are often found in transcription factors. Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified in a Moloney murine leukemia virus (MMLV) screen as a loci of common insertion mutagenesis that confers interleukin- (IL-2)-independent growth to IL-2-dependent T cell leukemias. Gfi1 deficiency is associated with lymphopenia while transgenic overexpression of Gfi1 can cooperate with other oncoproteins to rapidly transform lymphoid cells. Here, we report previously unknown Gfi1-dependent checkpoints in lymphoid development that are associated with an inability to integrate Notch1 signaling. Forced Notch signaling fails to rescue these defects and instead leads to synthetic lethality. The normal context for this synthetic lethal phenomenon is in lymphoid-primed hematopoietic progenitors and early T lineage precursors. Our results demonstrate Gfi1-/- defective lymphoid priming, and a significant reduction of early T lineage progenitors (ETP) that can be dissociated from previously-described defects in later stages of T lymphopoiesis. Failure to integrate Notch signaling is cell autonomous and most dramatic during early stages of T cell development. T-cell leukemia is thought to arise from arrested T cell progenitors at the same stage of development that acquire NOTCH1 mutations. As such, we investigated the requirement for Gfi1 in Notch1-driven T cell leukemia and found reduced transformation potential of oncogenic Notch initiated cultures after inducible deletion of Gfi1. Further, we report a positive association between the expression of NOTCH target genes and GFI1 expression in human T cell acute lymphoblastic leukemia (T-ALL) patients. This correlation is functional, because blockade of Gfi1 expression or function cures mice from lymphoid leukemia, impairs human T-ALL cell line growth, and reduces the expansion of primary human T-ALL xenografts in mice. In addition to integrating Notch signals, Gfi1 antagonizes the global expression of transcriptional targets of the pivotal p53 tumor suppressor, such as Bax, Pmaip1 and Bbc3, by directly interacting with p53 on the promoters of these genes. Oncogenic signaling in leukemic cells activates a p53-dependent DNA damage response and apoptosis, which is exacerbated in the absence of Gfi1. Gfi1 ablation enhances radiation therapy by accelerating p53-induced cell death. In sum, Gfi1 ablation lowers the threshold for p53-induced cell death. Targeting Gfi1 could increase the efficacy of radiation and chemotherapy and improve the outcome of T-ALL patients. Taken together, our data demonstrate novel roles for the transcriptional repressor Gfi1 in integrating Notch1 signaling in normal hematopoiesis and malignant transformation by globally repressing effectors of DNA damage and oncogenic stress that mediate cell death.
Leighton Grimes, PhD (Committee Chair)
Patrick Zweidler-McKay, MD PhD (Committee Member)
David Hildeman, PhD (Committee Member)
James Mulloy, PhD (Committee Member)
Marsha Wills-Karp, PhD (Committee Member)
204 p.
Biology
Gfi1; Notch; Leukemia; Hematopoiesis; T cell; p53;

Recommended Citations

Citations

  • Phelan, J. D. (2012). Transcriptional Control of Normal Lymphopoiesis and T-cell Neoplasia by Growth Factor Independent 1 [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1337351444

    APA Style (7th edition)

  • Phelan, James. Transcriptional Control of Normal Lymphopoiesis and T-cell Neoplasia by Growth Factor Independent 1. 2012. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1337351444.

    MLA Style (8th edition)

  • Phelan, James. "Transcriptional Control of Normal Lymphopoiesis and T-cell Neoplasia by Growth Factor Independent 1." Doctoral dissertation, University of Cincinnati, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1337351444

    Chicago Manual of Style (17th edition)

ucin1337351444
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© 2012, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.