Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K-dependent mechanisms synergizing in leukemogenic rearrangements

Shahar Biechonski, Dana Gourevich, Melanie Rall, Nasma Aqaqe, Muhammad Yassin, Adi Zipin-Roitman, Luba Trakhtenbrot, Leonid Olender, Yael Raz, Ariel J. Jaffa, Dan Grisaru, Lisa Wiesmuller, David Elad, Michael Milyavsky

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)864-876
Number of pages13
JournalInternational Journal of Cancer
Volume140
Issue number4
DOIs
StatePublished - 15 Feb 2017
Externally publishedYes

Keywords

  • DNA repair
  • MLLbcr
  • PI3K/Akt inhibitor
  • etoposide
  • hematopoietic stem cells
  • leukemia
  • quercetin
  • transplacental transfer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K-dependent mechanisms synergizing in leukemogenic rearrangements'. Together they form a unique fingerprint.

Cite this