PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia

Swee Heng Milon Pang, Martina Minnich, Pradnya Gangatirkar, Zhen Zheng, Anja Ebert, Guangchun Song, Ross A Dickins, Lynn M Corcoran, Charles G Mullighan, Meinrad Busslinger, Nicholas D Huntington, Stephen L Nutt, Sebastian Carotta

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27 Citations (Scopus)

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 languageEnglish
Pages (from-to)1375-1387
Number of pages13
JournalLeukemia
Volume30
Issue number6
DOIs
Publication statusPublished - 2016

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