Page 41 - 2019_04-Haematologica-web

Hematopoiesis
In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis
Eva-Maria Demmerath,1,* Sheila Bohler,1,2,* Mirjam Kunze3 and Miriam Erlacher1,4
*E-MD and SB contributed equally to this work.
ABSTRACT
Myelosuppression is a major and frequently dose-limiting side effect of anticancer therapy and is responsible for most treat- ment-related morbidity and mortality. In addition, repeated cycles of DNA damage and cell death of hematopoietic stem and pro- genitor cells, followed by compensatory proliferation and selection pres- sure, 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 immedi- ate complications and long-term sequelae. Epidermal growth factor (EGF) and prostaglandin E2 (PGE2) were reported to prevent chemo- or radiotherapy-induced myelosuppression in mice. We tested both mole- cules 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, 16,16-dimethyl-PGE2 (dmPGE2) did not accelerate regeneration of the human hematopoietic system in vivo. Repeated treatment of sublethally irradiated xenograft mice with known antiapoptotic substances, such as human FLT3L and thrombopoietin (TPO), which suppress transcription of the proapoptotic BCL-2 proteins BIM and BMF, also only marginally promoted human hematopoietic regeneration in vivo.
Introduction
Myelosuppression occurs transiently after intensive chemotherapy and radio- therapy, and is characterized by anemia, bleeding tendency and susceptibility to infection. It is a major and frequently dose-limiting side effect of anticancer therapy and is responsible for most treatment-related morbidity and mortality.1 In addition, repeated cycles of DNA damage, cell attrition and subsequent compensatory pro- liferation of hematopoietic stem and progenitor cells (HSPCs) lead to genomic instability and pave the way for late complications such as therapy-related myelodysplastic syndromes (t-MDS) and secondary acute myeloid leukemia (AML).2 Protection of HSPCs from chemo- and radiotherapy in patients with solid tumors would reduce both immediate complications and long-term sequelae.
Numerous endogenous pathways and chemical compounds have been reported to prevent chemo- or radiotherapy-induced myelosuppression in mice, either by
Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):669-677
1Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg; 2Faculty of Biology, University of Freiburg; 3Department of Obstetrics and Gynecology, University Medical Center of Freiburg and 4German Cancer Consortium (DKTK), Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
Correspondence:
MIRIAM ERLACHER
miriam.erlacher@uniklinik-freiburg.de
Received: February 18, 2018. Accepted: November 14, 2018. Pre-published: November 15, 2018.
doi:10.3324/haematol.2018.191569
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/669
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(4)
669
ARTICLE