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

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 γH2A.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 γH2A.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.