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Multiparametric analysis of etoposide exposed mesenchymal stem cells and Fanconi anemia cells: implications in development of secondary myeloid malignancy

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A Correction to this article was published on 09 September 2023

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Abstract

Secondary acute myeloid leukemia (sAML) may develop following a prior therapy or may evolve from an antecedent hematological disorder such as Fanconi Anemia (FA). Pathophysiology of leukemic evolution is not clear. Etoposide (Eto) is a chemotherapeutic agent implicated in development of sAML. FA is an inherited bone marrow (BM) failure disease characterized by genomic instability and xenobiotic susceptibility. Here, we hypothesized that alterations in the BM niche may play a critical/driver role in development of sAML in both conditions. Expression of selected genes involved in xenobiotic metabolism, DNA double-strand break response, endoplasmic reticulum (ER) stress, heat shock response and cell cycle regulation were determined in BM mesenchymal stem cells (MSCs) of healthy controls and FA patients at steady state and upon exposure to Eto at different concentrations and in recurrent doses. Expression of CYPA1, p53, CCNB1, Dicer1, CXCL12, FLT3L and TGF-Beta genes were significantly downregulated in FA-MSCs compared with healthy controls. Eto exposure induced significant alterations in healthy BM-MSCs with increased expression of CYP1A1, GAD34, ATF4, NUPR1, CXCL12, KLF4, CCNB1 and nuclear localization of Dicer1. Interestingly, FA-MSCs did not show significant alterations in these genes upon Eto exposure. As opposed to healthy MSCs DICER1 gene expression and intracellular localization was not altered on FA BM-MSCs after Eto treatment. These results showed that Eto is a highly potent molecule and has pleiotropic effects on BM-MSCs, FA cells show altered expression profile compared to healthy controls and Eto exposure on FA cells shows differential profile than healthy controls.

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Abbreviations

sAML:

Secondary acute myeloid leukemia

AML:

Acute myeloid leukemia

BM:

Bone marrow

BrDU:

Bromodeoksiüridin

DSB:

Double-strand breaks

Eto:

Etoposide

FA:

Fanconi anemia

HSC:

Hematopoietic stem cell

MSC:

Mesenchymal stem cell

SA-Beta-Gal:

Senescence associated beta-galactosidase

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Acknowledgements

We thank BMT Unit of Childrens Hospital of Hacettepe University for providing bone marrow samples of healthy donors and Fanconi patients.

Funding

This study has been supported by Hacettepe University Scientific Research Projects Coordination Unit with project Number: THD-2019–17607 and partially supported by Turkish Academy of Sciences (TUBA).

Author information

Author notes

  1. Buse Nurten Özel

    Present address: Institute for Genomic Medicine, Columbia University, New York, NY, USA

Authors and Affiliations

  1. Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, 06100 Gevher Nesibe Street, Sihhiye, Altındağ, Ankara, Turkey

    Cansu Özdemir, Bihter Muratoğlu, Buse Nurten Özel, Esin Alpdündar-Bulut, Gülsena Tonyalı & Duygu Uçkan-Çetinkaya

  2. Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, 06100 Gevher Nesibe Street, Sihhiye, Altındağ, Ankara, Turkey

    Bihter Muratoğlu, Gülsena Tonyalı & Duygu Uçkan-Çetinkaya

  3. Division of Hematology-Oncology, Faculty of Medicine, Department of Pediatrics, Hacettepe University, 06100 Gevher Nesibe Street, Sihhiye, Altındağ, Ankara, Turkey

    Esin Alpdündar-Bulut, Şule Ünal & Duygu Uçkan-Çetinkaya

  4. Research Center for Fanconi Anemia and Other IBMFSs, Hacettepe University, 06100 Gevher Nesibe Street, Sihhiye, Altındağ, Ankara, Turkey

    Şule Ünal & Duygu Uçkan-Çetinkaya

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Contributions

DUÇ, CÖ and BNÖ were involved in conceptualization; CÖ, BNÖ, EAB, GT and BM helped in methodology; CÖ, BNÖ and BM contributed to formal analysis and investigation; CÖ and DUÇ helped in writing—original draft; DUÇ, ŞÜ and BNÖ contributed to review and editing; CÖ, BM and DUÇ were involved in ; DUÇ and CÖ helped in supervision; Ş.Ü provided FA patient samples

Corresponding authors

Correspondence to Cansu Özdemir or Duygu Uçkan-Çetinkaya.

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Conflicts of interest

The authors declare that there is no conflict of interest.

Ethical approval

Signed informed consent for collection, storage and use of cells for research purposes was obtained and the study was approved by the Institutional Review Board of Hacettepe University (Study approval number: GO 21/230 and GO18/916–35).

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Informed consent was obtained from all individual participants/their parents included in the study.

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Özdemir, C., Muratoğlu, B., Özel, B.N. et al. Multiparametric analysis of etoposide exposed mesenchymal stem cells and Fanconi anemia cells: implications in development of secondary myeloid malignancy. Clin Exp Med 23, 4511–4524 (2023). https://doi.org/10.1007/s10238-023-01087-0

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