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

• Published in: Leukemia 2016-06, Vol.30 (6), p.1375-1387
• Main Authors: Pang, S H M, Minnich, M, Gangatirkar, P, Zheng, Z, Ebert, A, Song, G, Dickins, R A, Corcoran, L M, Mullighan, C G, Busslinger, M, Huntington, N D, Nutt, S L, Carotta, S
• Format: Article
• Language: English
• Subjects: 38/39; 631/136/142; 631/67/1990/283/2125; 64/110; 64/60; Acute lymphoblastic leukemia; Animals; B cells; B-Lymphocytes - cytology; Bone marrow; Cancer Research; Care and treatment; Clonal deletion; Critical Care Medicine; Deoxyribonucleic acid; Development and progression; DNA; ETS protein; Gene expression; Gene Expression Regulation; Gene sequencing; Genes; Genetic aspects; Health aspects; Hematology; Ikaros protein; Intensive; Interferon; Interferon regulatory factor; Interferon regulatory factor 4; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - physiology; Internal Medicine; Leukemia; Lymphatic leukemia; Lymphocytes B; Lymphocytic leukemia; Lymphopoiesis; Medical research; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Nucleotide sequence; Oncology; original-article; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - prevention & control; Progenitor cells; Properties; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; PU.1 protein; Stem cells; Trans-Activators - genetics; Trans-Activators - physiology; Transcription factors; Tumor suppressor genes; Tumors
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.27

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.