Cooperation of IRF-4 and IRF-8 deficiencies in the development of hematological malignancies. Mus musculus

We found that mice deficient in both IRF-4 and IRF-8 develop from a very early age a more aggressive CML-like disease than mice deficient in IRF-8 alone. IRF-4 deficiency dramatically enhanced the effect of IRF-8 deficiency on expansion of granulocyte-monocyte progenitors (GMPs). All mice deficient in both IRF-4 and IRF-8 eventually develop and succumb to a B-lymphoblastic leukemia/lymphoma at approximately 25 weeks of age. The results demonstrate that IRF-4 and IRF-8 deficiencies can cooperate in the development of both myeloid and lymphoid tumors. To gain insights into how loss of IRF-4 affects the transcriptional program underlying leukemogenesis, we analyzed the genome-wide transcription profiles of GMPs from WT, IRF-8 KO and IRF-4/8 DKO mice. Microarray analysis revealed genes differentially expressed in IRF-4/8 DKO and IRF-8 KO GMPs, including genes that are involved in cell growth regulation and/or tumorigenesis. Overall design: Total RNA was extracted from GMPs (Lin-/IL-7R-/Sca1-/Kit+/CD34+/FcRII/IIIhi) of wild type, IRF8 KO and IRF4/8 DKO mice (two samples each group) using the Qiagen RNAeasy Micro kit. Affymetrix Mouse Genome 430 2.0 microarray with 45,000 probe sets was used at the BIDMC Genomics Center. Hybridization data were normalized and expression values were determined using the PM/MM difference model by dChip 1.3 (DNA-Chip analyzer).