Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia

Although the role of promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) fusion protein is well recognized in acute promyelocytic leukemia (APL), its contribution to initiation and maintenance of leukemogenesis is not completely understood. Transcriptome analysis in the murine MRP8-PML/RARA APL model has demonstrated modest alterations in gene expression accompanied by expansion of the promyelocyte compartment. Of particular interest, mice expressing PML/RARA showed downregulation of the transcription factor Irf8 mRNA. Interferon regulatory factor 8 (IRF8) is a known regulator of hematopoiesis. Previous research had implicated IRF8 as a tumor suppressor for myeloid neoplasia, and mice lacking IRF8 develop a well-differentiated myeloproliferative neoplasm characterized by expansion of neutrophilic lineage cells. We hypothesized that PML/RARA-mediated downregulation of Irf8 transcript levels contributes to the initiation of APL. We observed significant downregulation of IRF8 protein levels in highly purified promyelocyte populations of PML/RARA transgenic mice. We also found that loss of IRF8 results in expansion of promyelocytes in vivo, partially phenocopying the impact of PML/RARA expression. Moreover, survival experiments showed that complete loss of IRF8 leads to acceleration of APL onset in our PML/RARA mice. Collectively, these data identify IRF8 downregulation as an important factor in APL initiation and highlight a tumor-suppressor role for IRF8 in this acute leukemia.