Loss of Wilms tumor 1 protein is a marker for apoptosis in response to replicative stress in leukemic cells

Miriam Pons, Claudia M. Reichardt, Dorle Hennig, Abinaya Nathan, Nicole Kiweler, Carol Stocking, Christian Wichmann, Markus Christmann, Falk Butter, Sigrid Reichardt, Günter Schneider, Thorsten Heinzel, Christoph Englert, Jörg Hartkamp, Oliver H. Krämer*, Nisintha Mahendrarajah

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

A remaining expression of the transcription factor Wilms tumor 1 (WT1) after cytotoxic chemotherapy indicates remaining leukemic clones in patients. We determined the regulation and relevance of WT1 in leukemic cells exposed to replicative stress and DNA damage. To induce these conditions, we used the clinically relevant chemotherapeutics hydroxyurea and doxorubicin. We additionally treated cells with the pro-apoptotic kinase inhibitor staurosporine. Our data show that these agents promote apoptosis to a variable extent in a panel of 12 leukemic cell lines and that caspases cleave WT1 during apoptosis. A chemical inhibition of caspases as well as an overexpression of mitochondrial, anti-apoptotic BCL2 family proteins significantly reduces the processing of WT1 and cell death in hydroxyurea-sensitive acute promyelocytic leukemia cells. Although the reduction of WT1 correlates with the pharmacological efficiency of chemotherapeutics in various leukemic cells, the elimination of WT1 by different strategies of RNA interference (RNAi) does not lead to changes in the cell cycle of chronic myeloid leukemia K562 cells. RNAi against WT1 does also not increase the extent of apoptosis and the accumulation of γH2AX in K562 cells exposed to hydroxyurea. Likewise, a targeted genetic depletion of WT1 in primary oviduct cells does not increase the levels of γH2AX. Our findings position WT1 as a downstream target of the apoptotic process that occurs in response to cytotoxic forms of replicative stress and DNA damage.

Original languageEnglish
Pages (from-to)2119-2135
Number of pages17
JournalArchives of Toxicology
Volume92
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018
Externally publishedYes

Keywords

  • Apoptosis
  • Caspase
  • DNA damage
  • Hydroxyurea
  • Leukemia
  • Replicative stress
  • WT1

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