BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib

Isabella Faraoni, Mirco Compagnone, Serena Lavorgna, Daniela Francesca Angelini, Maria Teresa Cencioni, Eleonora Piras, Paola Panetta, Tiziana Ottone, Susanna Dolci, Adriano Venditti, Grazia Graziani, Francesco Lo-Coco

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)462-472
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

Fingerprint

Acute Myeloid Leukemia
Biomarkers
Cell Line
olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Myeloid Cells
Histones
Blood Cells
Cell Death
Bone Marrow
Phosphorylation
Tissue Donors
Lymphocytes
Drug Therapy
Messenger RNA
Pharmaceutical Preparations
Neoplasms
Proteins

Keywords

  • Acute myeloid leukemia
  • BRCA1
  • H2AX
  • Olaparib
  • PARP inhibitor
  • PARP1

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

BRCA1, PARP1 and γH2AX in acute myeloid leukemia : Role as biomarkers of response to the PARP inhibitor olaparib. / Faraoni, Isabella; Compagnone, Mirco; Lavorgna, Serena; Angelini, Daniela Francesca; Cencioni, Maria Teresa; Piras, Eleonora; Panetta, Paola; Ottone, Tiziana; Dolci, Susanna; Venditti, Adriano; Graziani, Grazia; Lo-Coco, Francesco.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1852, No. 3, 01.03.2015, p. 462-472.

Research output: Contribution to journalArticle

Faraoni, I, Compagnone, M, Lavorgna, S, Angelini, DF, Cencioni, MT, Piras, E, Panetta, P, Ottone, T, Dolci, S, Venditti, A, Graziani, G & Lo-Coco, F 2015, 'BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1852, no. 3, pp. 462-472. https://doi.org/10.1016/j.bbadis.2014.12.001
Faraoni, Isabella ; Compagnone, Mirco ; Lavorgna, Serena ; Angelini, Daniela Francesca ; Cencioni, Maria Teresa ; Piras, Eleonora ; Panetta, Paola ; Ottone, Tiziana ; Dolci, Susanna ; Venditti, Adriano ; Graziani, Grazia ; Lo-Coco, Francesco. / BRCA1, PARP1 and γH2AX in acute myeloid leukemia : Role as biomarkers of response to the PARP inhibitor olaparib. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2015 ; Vol. 1852, No. 3. pp. 462-472.
@article{73102d829a024e8d905f3d41a8b480bd,
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.",
keywords = "Acute myeloid leukemia, BRCA1, H2AX, Olaparib, PARP inhibitor, PARP1",
author = "Isabella Faraoni and Mirco Compagnone and Serena Lavorgna and Angelini, {Daniela Francesca} and Cencioni, {Maria Teresa} and Eleonora Piras and Paola Panetta and Tiziana Ottone and Susanna Dolci and Adriano Venditti and Grazia Graziani and Francesco Lo-Coco",
year = "2015",
month = "3",
day = "1",
doi = "10.1016/j.bbadis.2014.12.001",
language = "English",
volume = "1852",
pages = "462--472",
journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",
issn = "0925-4439",
publisher = "Elsevier",
number = "3",

}

TY - JOUR

T1 - BRCA1, PARP1 and γH2AX in acute myeloid leukemia

T2 - Role as biomarkers of response to the PARP inhibitor olaparib

AU - Faraoni, Isabella

AU - Compagnone, Mirco

AU - Lavorgna, Serena

AU - Angelini, Daniela Francesca

AU - Cencioni, Maria Teresa

AU - Piras, Eleonora

AU - Panetta, Paola

AU - Ottone, Tiziana

AU - Dolci, Susanna

AU - Venditti, Adriano

AU - Graziani, Grazia

AU - Lo-Coco, Francesco

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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.

AB - 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.

KW - Acute myeloid leukemia

KW - BRCA1

KW - H2AX

KW - Olaparib

KW - PARP inhibitor

KW - PARP1

UR - http://www.scopus.com/inward/record.url?scp=84920089489&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920089489&partnerID=8YFLogxK

U2 - 10.1016/j.bbadis.2014.12.001

DO - 10.1016/j.bbadis.2014.12.001

M3 - Article

C2 - 25483710

AN - SCOPUS:84920089489

VL - 1852

SP - 462

EP - 472

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

IS - 3

ER -