KLF4 acts as a tumor suppressor in human B-cells and patients\' B-cell leukemias growing in mice

Transcription factor Kruppel-like factor 4 (KLF4) regulates numerous basic biological processes and acts either as an oncogene or tumor suppressor. To characterize the functional role of KLF4 in B-cell transformation, we infected primary naive B-cells with Epstein Barr virus (EBV), which is accompanied by rapid loss of KLF4 expression. EBV variants re-combinantly expressing KLF4 were unable to transform B-cells into lymphoblastoid cells, indicating a tumor suppressor function. To study established B-cell tumors, we developed a novel technique allowing the inducible KLF4 expression in patient-derived xenograft (PDX) B-cell acute lymphoblastic leukemia (ALL) cells, for competitive in vivo trials. Wild type, but not mutant KLF4 reduced leukemia proliferation, with strongest effects in mice pre-treated with conventional chemotherapy and at minimal residual disease. Re-expression of KLF4 reduced stem cell potential and sensitized cells towards systemic chemotherapy in vivo. Azacitidine upregulated KLF4 levels and knock-out of KLF4 in PDX B-ALL cells reduced Azacitidine-induced cell death, suggesting that KLF4, at least in part, mediates the anti-tumor effects of Azacitidine. Taken together, KLF4 acts as a tumor suppressor during EBV-induced lymphomagenesis and represents an interesting vulnerability in established B-ALL leukemias. As direct translational consequence, our data support applying Azacitidine in patients with B-ALL, to therapeutically target KLF4.