The University of Chicago Research Funding

• Principal Investigator: Barbara Kee, PhD, Associate Professor, Department of Pathology/MPMM, Committee on Immunology, Committee on Cancer Biology
• Start Date: May 8, 2009
• Total Award Amount: $380,356 (first year) $380,356 (second year)

Public Health Relevance

B-and T-lymphocyte are essential components of the adaptive immune response. We will examine the mechanism by which two essential transcriptional regulatory proteins enforce lineage appropriate expression during development of these lymphocyte lineages. Our studies will provide insight into how to how these proteins contribute to immune deficiency and transformation and how therapeutic interventions will impact lymphocyte gene expression and development.

Project Description

An outstanding question in lymphocyte developmental biology is how a cell with multiple differentiation options becomes restricted to a single developmental fate. Understanding how B- and T-lymphocyte lineage restriction occurs is also clinically relevant since mistakes in these programs can lead to severe disease such as immune deficiency or leukemia/lymphoma.

Therefore, to design effective therapies to intervene in disease and to predict the effects of therapeutic intervention on lymphocyte development we need to gain a mechanistic understanding of the factors that control lymphopoiesis. The E2A transcription factors are essential regulators of both B- and T-lymphocyte development. The Notch1 receptor is essential for promoting T-lymphopoiesis but suppresses B-lymphopoiesis and has been suggested to function through repression of E2A. Nonetheless, how E2A and/or Notch signaling function to promote the B- or T-lymphocyte fate remains a major question in lymphocyte development. Here we propose experiments to determine how E2A and Notch1 contribute to gene expression in lymphoid progenitors.

In Aim 1 we test the hypothesis that Notch signaling prevents E2A-dependent activation of the essential B-lymphocyte transcription factor early B cell factor (Ebf1) by preventing histone modifications that are required for E2A to access its binding site in the Ebf1 promoter. In Aim 2 we will test the hypothesis that E2A and Notch1 play opposing roles in the regulation of Ccr9, a chemokine receptors whose proper regulation is essential for T-cell development. Our experiments will provide important insight into the molecular mechanisms underlying lymphocyte cell fate decisions and how two critical regulators of this process coordinate to set up an appropriate lineage specific gene program.

This award is funded under the American Recovery and Reinvestment Act of 2009, NIH Award number: 1R01AI079213-01