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|Title:||PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia|
|Citation:||Leukemia, 2016; 30(6):1375-1387|
|Publisher:||Nature Publishing Group|
|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|
|Appears in Collections:||Medicine publications|
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