IRF-4 functions as a tumor suppressor in early B-cell development.
Interferon regulatory factor-4 (IRF-4) is a hematopoietic cell-restricted transcription factor important for hematopoietic development and immune response regulation. It was also originally identified as the product of a proto-oncogene involved in chromosomal translocations in multiple myeloma. In contrast to its oncogenic function in late stages of B lymphopoiesis, expression of IRF-4 is down-regulated in certain myeloid and early B-lymphoid malignancies. In this study, we found that the IRF-4 protein levels are increased in lymphoblastic cells transformed by the BCR/ABL oncogene in response to BCR/ABL tyrosine kinase inhibitor imatinib. We further found that IRF-4 deficiency enhances BCR/ABL transformation of B-lymphoid progenitors in vitro and accelerates disease progression of BCR/ABL-induced acute B-lymphoblastic leukemia (B-ALL) in mice, whereas forced expression of IRF-4 potently suppresses BCR/ABL transformation of B-lymphoid progenitors in vitro and BCR/ABL-induced B-ALL in vivo. Further analysis showed that IRF-4 inhibits growth of BCR/ABL+ B lymphoblasts primarily through negative regulation of cell-cycle progression. These results demonstrate that IRF-4 functions as tumor suppressor in early B-cell development and may allow elucidation of new molecular pathways significant to the lymphoid leukemogenesis by BCR/ABL. The context dependent roles of IRF-4 in oncogenesis should be an important consideration in developing cancer therapies targeting IRF-4.
Acquaviva
Jaime
J
Rosenstiel Basic Medical Sciences Research Center and Department of Biology, Brandeis University, Waltham, MA 02454-9110, USA.
Chen
Xiaoren
X
Ren
Ruibao
R
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D001483:Base Sequence; D001549:Benzamides; D016026:Bone Marrow Transplantation; D002051:Burkitt Lymphoma / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D002454:Cell Differentiation; D002460:Cell Line; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D016044:Fusion Proteins, bcr-abl; D016313:Genes, abl; D000068877:Imatinib Mesylate; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D014170:Transformation, Genetic; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
D001549:Benzamides; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D050835:Interferon Regulatory Factors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D025521:Tumor Suppressor Proteins; D000099218:Interferon Regulatory Factor-4