Purging human ovarian cortex of contaminating leukaemic cells by targeting the mitotic catastrophe signalling pathway

Lotte Eijkenboom, Callista Mulder, Bert van der Reijden, Norah van Mello, Julia van Leersum, Thessa Koorenhof-Scheele, Didi Braat, Catharina Beerendonk, Ronald Peek

Research output: Contribution to journalArticle*Academicpeer-review

Abstract

Purpose: Is it possible to eliminate metastasised chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cells from ovarian cortex fragments by inhibition of Aurora B/C kinases (AURKB/C) without compromising ovarian tissue or follicles? Methods: Human ovarian cortex tissue with experimentally induced tumour foci of CML, AML and primary cells of AML patients were exposed to a 24h treatment with 1 μM GSK1070916, an AURKB/C inhibitor, to eliminate malignant cells by invoking mitotic catastrophe. After treatment, the inhibitor was removed, followed by an additional culture period of 6 days to allow any remaining tumour cells to form new foci. Ovarian tissue integrity after treatment was analysed by four different assays. Appropriate controls were included in all experiments. Results: Foci of metastasised CML and AML cells in ovarian cortex tissue were severely affected by a 24h ex vivo treatment with an AURKB/C inhibitor, leading to the formation of multi-nuclear syncytia and large-scale apoptosis. Ovarian tissue morphology and viability was not compromised by the treatment, as no significant difference was observed regarding the percentage of morphologically normal follicles, follicular viability, glucose uptake or in vitro growth of small follicles between ovarian cortex treated with 1 μM GSK1070916 and the control. Conclusion: Purging of CML/AML metastases in ovarian cortex is possible by targeting the Mitotic Catastrophe Signalling Pathway using GSK1070916 without affecting the ovarian tissue. This provides a therapeutic strategy to prevent reintroduction of leukaemia and enhances safety of autotransplantation in leukaemia patients currently considered at high risk for ovarian involvement.

Original languageEnglish
Pages (from-to)1571-1588
Number of pages18
JournalJournal of assisted reproduction and genetics
Volume38
Issue number6
Early online date2021
DOIs
Publication statusPublished - Jun 2021

Keywords

  • Aurora kinases
  • Cryopreservation
  • GSK1070916
  • Myeloid leukaemia
  • Ovarian cortex
  • Purging

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