title: Poly (ADP-ribose) polymerase inhibitors selectively induce cytotoxicity in TCF3-HLF-positive leukemic cells.
abstract: Poly (ADP-ribose) polymerase (PARP) is an indispensable component of the DNA repair machinery. PARP inhibitors are used as cutting-edge treatments for patients with homologous recombination repair (HRR)-defective breast cancers harboring mutations in BRCA1 or BRCA2. Other tumors defective in HRR, including some hematological malignancies, are predicted to be good candidates for treatment with PARP inhibitors. Screening of leukemia-derived cell lines revealed that lymphoid lineage-derived leukemia cell lines, except for those derived from mature B cells and KMT2A (MLL)-rearranged B-cell precursors, were relatively sensitive to PARP inhibitors. By contrast, acute myelogenous leukemia cell lines, except for RUNX1-RUNXT1 (AML1-ETO)-positive lines, were relatively resistant. Intriguingly, TCF3 (E2A)-HLF-positive leukemia was sensitive to PARP inhibitors. TCF3-HLF expression suppressed HRR activity, suggesting that PARP inhibitor treatment induced synthetic lethality. Furthermore, TCF3-HLF expression decreased levels of MCPH1, which regulates the expression of BRCA1, resulting in attenuation of HRR activity. The PARP inhibitor olaparib was also effective in an in vivo xenograft model. Our results suggest a novel therapeutic approach for treating refractory leukemia, particularly the TCF3-HLF-positive subtype.
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Piao
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Takai
authors.affiliation: Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, 119228, Singapore.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kamiya
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Yamanashi University, Yamanashi Chuo, 1110 Shimokato, Yamanashi, 409-3898, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inukai
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Yamanashi University, Yamanashi Chuo, 1110 Shimokato, Yamanashi, 409-3898, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Sugita
authors.affiliation: Department of Hematology, Tokyo Medical University, Nishi-Shinjuku 6-7-1, Shinjuku-ku, Tokyo, 160-0023, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Experimental Oncology, Via G. Venezian 1, Milan, 20133, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.affiliation: Department of Frontier Life Science, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8519, Japan. Electronic address: skkmiz@gmail.com.
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8519, Japan. Electronic address: m.takagi.ped@tmd.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D019070:Cell Lineage; D003598:Cytoskeletal Proteins; D053903:DNA Breaks, Double-Stranded; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059767:Recombinational DNA Repair; D013997:Time Factors; D014162:Transfection; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; C578540:TCF3-HLF fusion protein, human; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: Acute lymphoblastic leukemia; Homologous recombination repair; PARP inhibitor; TCF3-HLF