Projects per year
Abstract
The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements. Although all three factors are expressed from the onset of B-cell development, single deficiency of these factors in B-cell progenitors only mildly impacts on bone marrow B lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B-cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B-cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B-cell numbers. Strikingly, all PU.1/IRF4 and 50 of PU.1/IRF8 double deficient mice developed pre-B-cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B-cell development and to prevent pre-B-ALL formation.Leukemia advance online publication, 11 March 2016; doi:10.1038/leu.2016.27.
Original language | English |
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Pages (from-to) | 1375-1387 |
Number of pages | 13 |
Journal | Leukemia |
Volume | 30 |
Issue number | 6 |
DOIs | |
Publication status | Published - 2016 |
Projects
- 1 Finished
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A Systems Approach to the Adaptive Immune Response
Hodgkin, P. D., Corcoran, L. M., Tarlinton, D., Belz, G. T. & Nutt, S. L.
1/01/14 → 31/12/18
Project: Research