title: shRNA screening identifies JMJD1C as being required for leukemia maintenance.
abstract: Epigenetic regulatory mechanisms are implicated in the pathogenesis of acute myeloid leukemia (AML) and acute lymphoid leukemia (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 short hairpin RNA (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.
authors: Biotech Research and Innovation Centre.
authors: Patrycja
authors: P
authors: Sroczynska
authors: V Adam
authors: VA
authors: Cruickshank
authors: John-Paul
authors: JP
authors: Bukowski
authors: Satoru
authors: S
authors: Miyagi
authors: Frederik Otzen
authors: FO
authors: Bagger
authors: Julian
authors: J
authors: Walfridsson
authors: Mikkel Bruhn
authors: MB
authors: Schuster
authors: Bo
authors: B
authors: Porse
authors: Kristian
authors: K
authors: Helin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D020570:Genes, myb; D016259:Genes, myc; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics*; D007942:Leukemia, Experimental / Q000235:genetics / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014410:Tumor Stem Cell Assay
chemical_list: C497422:KMT2A protein, human; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; C520448:JMJD1C protein, human; C554520:JMJD1c protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; D010089:Oxidoreductases, N-Demethylating; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse