1 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet2 The Danish Stem Cell Center, Faculty of Health and Medical Sciences, Københavns Universitet3 Porse Group, BRIC Research Groups, BRIC, Københavns Universitet4 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet5 Administration, BRIC Administration, BRIC, Københavns Universitet6 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet7 unknown8 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet9 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet10 Porse Group, BRIC Research Groups, BRIC, Københavns Universitet
Epigenetic regulatory mechanisms are implicated in the pathogenesis of acute myeloid and lymphoid leukemia (AML and ALL). Recent progress suggests that proteins involved in epigenetic control are amenable to drug intervention, but little is known about the cancer-specific dependency on epigenetic regulators for cell survival and proliferation. We used a mouse model of human AML induced by the MLL-AF9 fusion oncogene, and an epigenetic shRNA library to screen for novel potential drug targets. As a counter-screen for general toxicity of shRNAs, we used normal mouse bone marrow cells. One of the best candidate drug targets identified in these screens was Jmjd1c. Depletion of Jmjd1c impairs growth and colony formation of mouse MLL-AF9 cells in vitro, as well as establishment of leukemia after transplantation. Depletion of JMJD1C impairs expansion and colony formation of human leukemic cell lines, with the strongest effect observed in the MLL-rearranged ALL cell line, SEM. In both mouse and human leukemic cells, the growth defect upon JMJD1C depletion appears to be primarily due to increased apoptosis, which implicates JMJD1C as a potential therapeutic target in leukemia.
Blood (online), 2014, Vol 123, Issue 12, p. 1870-82