Cooperation between deficiencies of IRF-4 and IRF-8 promotes both myeloid and lymphoid tumorigenesis.
Interferon regulatory factor 4 (IRF-4) plays important functions in B- and T-cell development and immune response regulation and was originally identified as the product of a proto-oncogene involved in chromosomal translocations in multiple myeloma. Although IRF-4 is expressed in myeloid cells, its function in that lineage is not known. The closely related family member IRF-8 is a critical regulator of myelopoiesis, which when deleted in mice results in a syndrome highly similar to human chronic myelogenous leukemia. In early lymphoid development, we have shown previously that IRF-4 and IRF-8 can function redundantly. We therefore investigated the effects of a combined loss of IRF-4 and IRF-8 on hematologic tumorigenesis. We found that mice deficient in both IRF-4 and IRF-8 develop from a very early age a more aggressive chronic myelogenous leukemia-like disease than mice deficient in IRF-8 alone, correlating with a greater expansion of granulocyte-monocyte progenitors. Although these results demonstrate, for the first time, that IRF-4 can function as tumor suppressor in myeloid cells, interestingly, all mice deficient in both IRF-4 and IRF-8 eventually develop and die of a B-lymphoblastic leukemia/lymphoma. Combined losses of IRF-4 and IRF-8 therefore can cooperate in the development of both myeloid and lymphoid tumors.
Jo
Seung-Hee
SH
Rosenstiel Basic Medical Sciences Research Center and Department of Biology, Brandeis University, Waltham, MA, USA.
Schatz
Jonathan H
JH
Acquaviva
Jaime
J
Singh
Harinder
H
Ren
Ruibao
R
D000818:Animals; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000172:deficiency* / Q000235:genetics; D015448:Leukemia, B-Cell / Q000209:etiology* / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000473:pathology; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4; C000715470:MAS1 protein, human