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https://hdl.handle.net/2440/103600
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Type: | Journal article |
Title: | PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia |
Author: | Pang, S. Minnich, M. Gangatirkar, P. Zheng, Z. Ebert, A. Song, G. Dickins, R. Corcoran, L. Mullighan, C. Busslinger, M. Huntington, N. Nutt, S. Carotta, S. |
Citation: | Leukemia, 2016; 30(6):1375-1387 |
Publisher: | Nature Publishing Group |
Issue Date: | 2016 |
ISSN: | 1476-5551 1476-5551 |
Statement of Responsibility: | SHM Pang, M Minnich, P Gangatirkar, Z Zheng, A Ebert, G Song, RA Dickins, LM Corcoran, CG Mullighan, M Busslinger, ND Huntington, SL Nutt and S Carotta |
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. |
Keywords: | B-Lymphocytes Animals Mice, Knockout Mice Trans-Activators Proto-Oncogene Proteins Lymphopoiesis Gene Expression Regulation Interferon Regulatory Factors Precursor B-Cell Lymphoblastic Leukemia-Lymphoma |
Rights: | © 2016 Macmillan Publishers Limited All rights reserved |
DOI: | 10.1038/leu.2016.27 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1054925 http://purl.org/au-research/grants/nhmrc/637345 http://purl.org/au-research/grants/nhmrc/1058238 NHMRC |
Published version: | http://dx.doi.org/10.1038/leu.2016.27 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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