Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K-dependent mechanisms synergizing in leukemogenic rearrangements.
Quercetin (Que) is an abundant flavonoid in the human diet and high-concentration food supplement with reported pro- and anti-carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the mixed lineage leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in hematopoietic stem and progenitor cells (HSPCs). However, molecular targets mediating Que effects on DNA repair relevant to MLL translocations have not been defined. In this study we describe novel and potentially genotoxic Que activities in suppressing non-homologous end joining and homologous recombination pathways downstream of MLL cleavage. Using pharmacological dissection of DNA-PK, ATM and PI3K signalling we defined PI3K inhibition by Que with a concomitant decrease in the abundance of key DNA repair genes to be responsible for DNA repair inhibition. Evidence for the downstream TopoII-independent mutagenic potential of Que was obtained by documenting further increased frequencies of MLL rearrangements in human HSPCs concomitantly treated with Etoposide and Que versus single treatments. Importantly, by engaging a tissue engineered placental barrier, we have established the extent of Que transplacental transfer and hence provided the evidence for Que reaching fetal HSPCs. Thus, Que exhibits genotoxic effects in human HSPCs via different mechanisms when applied continuously and at high concentrations. In light of the demonstrated Que transfer to the fetal compartment our findings are key to understanding the mechanisms underlying infant leukemia and provide molecular markers for the development of safety values.
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Shahar
S
Biechonski
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel.
Dana
D
Gourevich
Department of Obstetrics and Gynecology, Gynecological Oncology, University of Ulm, Ulm, Germany.
Melanie
M
Rall
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Nasma
N
Aqaqe
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Muhammad
M
Yassin
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Adi
A
Zipin-Roitman
Cancer Research Centre, Sheba Medical Centre, Tel Hashomer, Israel.
Luba
L
Trakhtenbrot
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Leonid
L
Olender
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Department of Obstetrics and Gynecology, Gynecologic Oncology Division, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Yael
Y
Raz
Ultrasound Unit in Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Ariel J
AJ
Jaffa
Department of Obstetrics and Gynecology, Gynecologic Oncology Division, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Dan
D
Grisaru
Department of Obstetrics and Gynecology, Gynecological Oncology, University of Ulm, Ulm, Germany.
Lisa
L
Wiesmuller
Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel.
David
D
Elad
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Michael
0000-0002-5083-0809
M
Milyavsky
D000328:Adult; D001205:Ascorbic Acid / Q000494:pharmacology; D018929:Cell Culture Techniques; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000032:analysis; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000139:chemically induced* / Q000235:genetics; D008431:Maternal-Fetal Exchange; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011247:Pregnancy; D011794:Quercetin / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D059005:Topoisomerase II Inhibitors / Q000633:toxicity*
D001205:Ascorbic Acid; D004250:DNA Topoisomerases, Type II; D005047:Etoposide; D019833:Genistein; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D051788:Myeloid-Lymphoid Leukemia Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011794:Quercetin; D059005:Topoisomerase II Inhibitors; C468783:H2AX protein, human; C497422:KMT2A protein, human
DNA repair; MLLbcr; PI3K/Akt inhibitor; etoposide; hematopoietic stem cells; leukemia; quercetin; transplacental transfer