Abstract
The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eμ-Myc model of Burkitt's lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eμ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eμ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.
Highlights
Runx1 encodes a transcription factor that plays a vital role in development of the haematopoietic system [1]
Addiction to Runx1 in primary Eμ-Myc lymphoma cells is attenuated in established cell lines
These mice were further crossed to generate Mx1Cre/Runx1fl/fl cohorts in which we could examine the ability of lymphoma cells to survive deletion of the endogenous Runx1 gene
Summary
Runx encodes a transcription factor that plays a vital role in development of the haematopoietic system [1] It belongs to a three-membered family of mammalian gene products that bind a common DNA target sequence by virtue of the conserved Runt domain and share a common heterodimeric binding co-factor, CBFβ [2, 3]. Like their Drosophila homologue, Runt, the Runx proteins function as transcriptional regulators and are capable of activating or repressing target promoters through the recruitment of co-activators or co-repressors [4]. The combination of Runx and Myc oncogenes appears to overcome the need for mutational inactivation of p53 [14] despite the fact that both genes can trigger the p53 pathway and collaborate with p53 loss when over-expressed individually [15, 16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
