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In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis
Eva-Maria Demmerath, Sheila Bohler, Mirjam Kunze, Miriam Erlacher
Haematologica November 2018 : haematol.2018.191569; doi:10.3324/haematol.2018.191569
Eva-Maria Demmerath
Dept. of Pediatrics and Adolescent MedicineUniversity Medical Center Freiburg;
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Sheila Bohler
Dept of Pediatrics & Adolescent Medicine, Faculty of Biology, University Medical Center Freiburg;
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Mirjam Kunze
Dept. of Obstetrics and Gynecology, University Medical Center Freiburg;
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Miriam Erlacher
University Medical Center Freiburg
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Author Affiliations

  1. Eva-Maria Demmerath1,
  2. Sheila Bohler2,
  3. Mirjam Kunze3 and
  4. Miriam Erlacher4,*
  1. 1 Dept. of Pediatrics and Adolescent MedicineUniversity Medical Center Freiburg;
  2. 2 Dept of Pediatrics & Adolescent Medicine, Faculty of Biology, University Medical Center Freiburg;
  3. 3 Dept. of Obstetrics and Gynecology, University Medical Center Freiburg;
  4. 4 University Medical Center Freiburg
  1. ↵* Corresponding author; email: miriam.erlacher{at}uniklinik-freiburg.de
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Abstract

Myelosuppression is a major and frequently dose limiting side-effect of anticancer therapy and responsible for most treatment-related morbidity and mortality. In addition, repeated cycles of DNA damage and cell death of hematopoietic stem and progenitor cells, followed by compensatory proliferation and selection pressure, lead to genomic instability and pave the way for therapy-related myelodysplastic syndromes and secondary acute myeloid leukemia. Protection of hematopoietic stem and progenitor cells from chemo- and radiotherapy in patients with solid tumors would reduce both immediate complications and long-term sequelae. EGF and PGE2 were reported to prevent chemo- or radiotherapy-induced myelosuppression in mice. We tested both molecules for potentially protective effects on human CD34+ cells in vitro and established a xenograft mouse model to analyze stress resistance and regeneration of human hematopoiesis in vivo. EGF was neither able to protect human stem and progenitor cells in vitro nor to promote hematopoietic regeneration following sublethal irradiation in vivo. PGE2 significantly reduced in vitro apoptotic susceptibility of human CD34+ cells to taxol and etoposide. This could, however, be ascribed to reduced proliferation rather than to a change in apoptosis signaling and BCL-2 protein regulation. Accordingly, dmPGE2 did not accelerate regeneration of the human hematopoietic system in vivo. Also repeated treatment of sublethally irradiated xenograft mice with known antiapoptotic substances such as human FLT3L and TPO, which suppress transcription of the proapoptotic BCL-2 proteins BIM and BMF, did only marginally promote human hematopoietic regeneration in vivo.

  • Received February 18, 2018.
  • Accepted November 14, 2018.
  • Copyright © 2018, Ferrata Storti Foundation
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Keywords

hematopoietic stem cell
Hematopoiesis
apoptosis

Vol 104 Issue 12

Haematologica: 104 (12)
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In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis
Eva-Maria Demmerath, Sheila Bohler, Mirjam Kunze, Miriam Erlacher
Haematologica Nov 2018, haematol.2018.191569; DOI: 10.3324/haematol.2018.191569

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Eva-Maria Demmerath, Sheila Bohler, Mirjam Kunze, Miriam Erlacher
Haematologica Nov 2018, haematol.2018.191569; DOI: 10.3324/haematol.2018.191569
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