title: BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib.
abstract: Olaparib (AZD-2281, Ku-0059436) is an orally bioavailable and well-tolerated poly(ADP-ribose) polymerase (PARP) inhibitor currently under investigation in patients with solid tumors. To study the clinical potential of olaparib as a single-agent for the treatment of acute myeloid leukemia (AML) patients, we analyzed the in vitro sensitivity of AML cell lines and primary blasts. Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples (88%) and tested cell lines. At these concentrations, olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and CD34-enriched peripheral blood cells obtained from healthy donors. Most primary AML analyzed were characterized by low BRCA1 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib. Noteworthy, while PARP1 over-expression was detected in blasts not responsive to olaparib, phosphorylation of the histone H2AFX (γH2AX) was associated with drug sensitivity. As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion. The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and/or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: faraoni@med.uniroma2.it.
authors.forename: Isabella
authors.initials: I
authors.lastname: Faraoni
authors.affiliation: Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: mircocomp@gmail.com.
authors.forename: Mirco
authors.initials: M
authors.lastname: Compagnone
authors.affiliation: Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy; Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy. Electronic address: serena.lavorgna@hotmail.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Lavorgna
authors.affiliation: Unit of Neuroimmunology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: df.angelini@gmail.com.
authors.forename: Daniela Francesca
authors.initials: DF
authors.lastname: Angelini
authors.affiliation: Unit of Neuroimmunology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: mt.cencioni@hsantalucia.it.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Cencioni
authors.affiliation: Unit of Neuroimmunology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy. Electronic address: e.piras@hsantalucia.it.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Piras
authors.affiliation: Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy; Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy. Electronic address: paolapanetta@yahoo.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Panetta
authors.affiliation: Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy; Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy. Electronic address: tizianaottone@hotmail.com.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ottone
authors.affiliation: Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy. Electronic address: dolci@uniroma2.it.
authors.forename: Susanna
authors.initials: S
authors.lastname: Dolci
authors.affiliation: Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy. Electronic address: adriano.venditti@uniroma2.it.
authors.forename: Adriano
authors.initials: A
authors.lastname: Venditti
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy. Electronic address: graziani@uniroma2.it.
authors.forename: Grazia
authors.initials: G
authors.lastname: Graziani
authors.affiliation: Unit of Neuro-Oncohematology, Santa Lucia Foundation-I.R.C.C.S., Rome, Italy; Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy. Electronic address: francesco.lo.coco@uniroma2.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002872:Chromosome Deletion; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: Acute myeloid leukemia; BRCA1; H2AX; Olaparib; PARP inhibitor; PARP1