Yang, Qi
(2010)
The Role of the Transcription Factor 3 Gene 3 Product E47 in Multipotent Hematopoietic Stem Cells and Progenitors.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
E47, an alternative splice product of the transcription factor 3 (TCF3) gene, has been mechanistically linked with multiple leukemias and lymphomas, and thus it is of great public health importance to study the mechanisms by which E47 influences the development of the hematopoietic system. Throughout life, all mature blood cells are constantly replenished from rare, self-renewing bone marrow hematopoietic stem cells (HSCs) and downstream non-renewing multipotent progenitors (MPPs). Little is known about the gene regulatory network that controls the integrity of these essential bone marrow subsets. Previous evidence has suggested a crucial role for the transcription factor E47 in lymphocyte lineage commitment. However, the specific stages of hematopoiesis that require E47 and the underlying mechanisms through which it acts on remain unclear. Our study aims to elucidate the role of the transcription factor E47 in the earliest, multipotent stages of hematopoiesis. Using E47 deficient mice, we found that E47 is required for the development and functional integrity of uncommitted hematopoietic progenitors. Our results showed that E47 deficient mice had a 50-70% reduction in non-renewing MPPs, and the residual MPPs failed to initiate V(D)J recombination, a hallmark of lymphoid lineage progression. The long-term lineage repopulation and self-renewal activities of the primitive HSCs are also compromised in the absence of E47. Not only were the in vivo long-term repopulating HSCs reduced by 3 fold in the bone marrow of E47 deficient mice, but also these HSCs displayed poor self-renewal efficiency by serial transplantation. The compromised self-renewal of E47 null HSCs appears to be associated with premature exhaustion due to over-proliferation under replication stress. The multipotent hematopoietic stem/progenitor cells from E47 deficient mice displayed a striking hyperproliferation following transplantation stress, and they exhibited increased susceptibility to in vivo challenge with a mitotoxic drug. Finally, loss of function and gain of function assays identified the cell cycle inhibitor p21 as a target gene of E47. Together, these observations suggested that E47 regulates the development and functional potential of multipotent hematopoietic subsets, probably through effects on p21-mediated cell cycle quiescence. These findings might provide novel mechanistic insights into hematopoietic damage repair and malignant transformation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
28 June 2010 |
| Date Type: |
Completion |
| Defense Date: |
10 January 2010 |
| Approval Date: |
28 June 2010 |
| Submission Date: |
27 January 2010 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
E47; hematopoietic stem cells; Transcription Factor 3 |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-01272010-143133/, etd-01272010-143133 |
| Date Deposited: |
10 Nov 2011 19:31 |
| Last Modified: |
19 Dec 2016 14:34 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/6313 |
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