Bone marrow hematopoietic stem cells continually seed the blood lineages throughout adult life. E47 is a major transcription factor whose activity is critical for the progression of uncommitted hematopoietic progenitors to the lymphoid lineages. Perturbations in E47 expression are also associated with blood cancers. We have found that mice lacking E47 have a profound depletion of bone marrow multipotent progenitors as well downstream lineage restricted populations. Primitive precursors from E47 deficient mice exhibit heightened proliferative activity but decreased expression of key markers associated with differentiation. Reciprocal gain of function and loss of function studies identify two key genes as candidate E47 targets: the cell cycle regulator p21 and the transcriptional regulator Ikaros. Here, we propose to establish the mechanistic relationship between E47 and these two factors in primary bone marrow precursor subsets.
In Aim 1, we focus on the proliferative defect and determine if E47 is a critical regulator of the balance between stem cell proliferation and self-renewal.
In Aim 2, we examine whether E47 and p21 collaborate in the same genetic pathway to regulate stem cell proliferation.
In Aim 3, we determine if Ikaros is the essential E47 target gene that regulates the differentiation of primary multipotent progenitors to the lymphoid lineages. Together, these aims address the molecular mechanisms that regulate the functional integrity of stem cells during lymphoid lineage progression. This work will provide new information about the molecular events that control stem cell integrity, and will provide key insight into the mechanisms by which dysregulation of E47 activity contributes to cancers of lymphoid origin. Public Health Relevance: The immune system is capable of responding to a vast array of potential pathogens. This is accomplished in part through the production of B and T lymphocytes. Our studies are aimed at elucidating the factors that regulate the functional integrity of hematopoietic stem cells during progression to the lymphocyte lineages.

Public Health Relevance

The immune system is capable of responding to a vast array of potential pathogens. This is accomplished in part through the production of B and T lymphocytes. Our studies are aimed at elucidating the factors that regulate the functional integrity of hematopoietic stem cells during progression to the lymphocyte lineages.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079047-05
Application #
8431442
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Nasseri, M Faraz
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$309,065
Indirect Cost
$101,773
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Santos, Patricia M; Ding, Ying; Borghesi, Lisa (2014) Cell-intrinsic in vivo requirement for the E47-p21 pathway in long-term hematopoietic stem cells. J Immunol 192:160-8
Borghesi, Lisa (2014) Hematopoiesis in steady-state versus stress: self-renewal, lineage fate choice, and the conversion of danger signals into cytokine signals in hematopoietic stem cells. J Immunol 193:2053-8
Boiko, Julie R; Borghesi, Lisa (2012) Hematopoiesis sculpted by pathogens: Toll-like receptors and inflammatory mediators directly activate stem cells. Cytokine 57:1-8
Santos, Patricia; Arumemi, Fortuna; Park, Kyung Soo et al. (2011) Transcriptional and epigenetic regulation of B cell development. Immunol Res 50:105-12
Kardava, Lela; Yang, Qi; St Leger, Anthony et al. (2011) The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells. Int Immunol 23:375-84
Kuhrt, David; Faith, Seth; Hattemer, Angela et al. (2011) Naive and memory B cells in the rhesus macaque can be differentiated by surface expression of CD27 and have differential responses to CD40 ligation. J Immunol Methods 363:166-76
Santos, Patricia M; Borghesi, Lisa (2011) Molecular resolution of the B cell landscape. Curr Opin Immunol 23:163-70
Esplin, Brandt L; Shimazu, Tomoyuki; Welner, Robert S et al. (2011) Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol 186:5367-75
Yang, Qi; Esplin, Brandt; Borghesi, Lisa (2011) E47 regulates hematopoietic stem cell proliferation and energetics but not myeloid lineage restriction. Blood 117:3529-38

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