High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023698%3A_____%2F25%3AN0000013" target="_blank" >RIV/00023698:_____/25:N0000013 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/25:10504427 RIV/00159816:_____/25:00082230 RIV/00216224:14110/25:00144750 RIV/00064165:_____/25:10504427 RIV/00023736:_____/25:00013830

Výsledek na webu

<a href="https://www.nature.com/articles/s41598-025-19454-0" target="_blank" >https://www.nature.com/articles/s41598-025-19454-0</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41598-025-19454-0" target="_blank" >10.1038/s41598-025-19454-0</a>

Jazyk výsledku

angličtina

Název v původním jazyce

High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes

Popis výsledku v původním jazyce

Autologous hematopoietic stem and progenitor cell (HSPC) transplantation is performed after myeloablation in cancer treatment to restore blood cell production and support immune recovery. Despite its success in achieving survivorship, many recipients later suffer from recurrent infections and pulmonary complications. The mechanisms driving the complications after HSPC transplantation later in life are unknown. However, the induction and/or maintenance therapeutics might be driving the negative outcomes in treated patients. We investigated the effects of the cancer therapeutics topotecan and 13-cis-retinoic acid (13cisRA) on cell phenotype and functions of HSPCs isolated from cord blood and primary monocytes from adult donors. In HSPCs, 13cisRA reduced autophagy and lysosomal activity, triggered a DNA damage response through increased gamma H2A.X and CDKN2 expression (including the spliced p14ARF isoform), and upregulated the epigenetic regulator SIRT3. 13cisRA also activated primary monocytes, inducing CXCL8 and CCL2 production. By contrast, topotecan had no effects on mature monocytes but induced DNA damage, metabolic remodeling, and epigenetic alterations in HSPCs. These changes included increased CDKN1A expression, higher gamma H2A.X-positive cell frequency, autophagy activation, and SIRT1 upregulation. The differential effects of 13cisRA and topotecan on HSPCs and monocytes might underlie the long-term complications of autologous HSPC transplantation. By modulating DNA damage, autophagy, and epigenetic pathways, these therapies could influence hematopoietic recovery and immune reconstitution, offering insights for improving transplantation outcomes.

Název v anglickém jazyce

High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes

Popis výsledku anglicky

Autologous hematopoietic stem and progenitor cell (HSPC) transplantation is performed after myeloablation in cancer treatment to restore blood cell production and support immune recovery. Despite its success in achieving survivorship, many recipients later suffer from recurrent infections and pulmonary complications. The mechanisms driving the complications after HSPC transplantation later in life are unknown. However, the induction and/or maintenance therapeutics might be driving the negative outcomes in treated patients. We investigated the effects of the cancer therapeutics topotecan and 13-cis-retinoic acid (13cisRA) on cell phenotype and functions of HSPCs isolated from cord blood and primary monocytes from adult donors. In HSPCs, 13cisRA reduced autophagy and lysosomal activity, triggered a DNA damage response through increased gamma H2A.X and CDKN2 expression (including the spliced p14ARF isoform), and upregulated the epigenetic regulator SIRT3. 13cisRA also activated primary monocytes, inducing CXCL8 and CCL2 production. By contrast, topotecan had no effects on mature monocytes but induced DNA damage, metabolic remodeling, and epigenetic alterations in HSPCs. These changes included increased CDKN1A expression, higher gamma H2A.X-positive cell frequency, autophagy activation, and SIRT1 upregulation. The differential effects of 13cisRA and topotecan on HSPCs and monocytes might underlie the long-term complications of autologous HSPC transplantation. By modulating DNA damage, autophagy, and epigenetic pathways, these therapies could influence hematopoietic recovery and immune reconstitution, offering insights for improving transplantation outcomes.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

<a href="/cs/project/NW24J-09-00054" target="_blank" >NW24J-09-00054: Nové metody posouzení kvality a fitness CD34+ buněk a CD34-derivovaných myeloidních buněk z mobilizované krve</a><br>

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

SCIENTIFIC REPORTS

ISSN

2045-2322

e-ISSN

2045-2322

Svazek periodika

15

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

18

Strana od-do

35723

Kód UT WoS článku

001593359600030

EID výsledku v databázi Scopus

2-s2.0-105018648560