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