B cell transcription factors define a novel tumor suppressor gene network in acute lymphoblastic leukemia (P4410)

We recently found that STAT5 activation correlates with poor response to therapy in B-ALL. To identify genetic defects that cooperate with STAT5 activation to initiate transformation we carried out a forward genetic screen involving the mutagenic transposon Sleeping Beauty. This screen identified a number of cooperating partners including gain-of-function mutations in Sos1 and loss-of-function mutations in Ebf1 and Ikzf1 (i.e., Ikaros). Haploinsufficiency of Ebf1 or the related transcription factor Pax5 synergized with STAT5 to rapidly induce progenitor B-ALL in 100% of mice. The leukemic cells displayed reduced expression of Ebf1 and Pax5, which affected a small subset of EBF1 or PAX5 target genes, including tumor suppressor genes and oncogenes. To test whether compound haploinsufficiency of Ebf1 and Pax5 alone is sufficient to cause transformation, we generated Ebf1+/- x Pax5+/- mice. Over 80% of these mice developed progenitor B-ALL. We observed similar results in Ebf1+/- x Ikzf1+/-, Pax5+/- x Ikzf1+/-, and Pax5+/- x Ebf1+/- x Ikzf1+/- mice; interestingly, although most leukemias were B-ALL we also observed T-ALL suggesting that T-All may arise from a B cell progenitor. Our findings suggest a model in which STAT5 activation cooperates with small perturbations in a self-reinforcing network of transcription factors critical for B cell development to initiate ALL and that loss of any two alleles in the network results in a loss of network tumor suppressor function.