Abstract
The process of oncogenesis leads to dysregulation of mRNA and protein levels of multiple molecules in tumor cells. A minority of them harbors an essential function and might represent attractive therapeutic targets. Unfortunately, clinic-close methods are lacking which validate alterations for their functional implications, at best in individual tumors. We developed a novel technique for inducible transgene expression in established patient-derived xenograft (PDX) models in vivo. Transcription factor Krüppel-like factor 4 (KLF4) acts either as an oncogene or tumor suppressor and its role in B-cell acute lymphoblastic leukemia (B-ALL) is insufficiently defined. In competitive pre-clinical in vivo trials, we found that re-expressing wild type, but not mutant control KLF4 reduced leukemia load in PDX models of B-ALL, with strongest effects after conventional chemotherapy, at minimal residual disease. Re-expressing KLF4 sensitized PDX models towards systemic chemotherapy in vivo. Of major translational relevance, Azacitidine upregulated KLF4 levels and knockout of KLF4 in PDX models reduced Azacitidine-induced cell death, suggesting that Azacitidine acts via KLF4. Taken together, our novel technique enabled identifying an essential role for KLF4 in established B-ALL leukemias and support applying Azacitidine in patients with B-ALL, for therapeutically targeting KLF4.