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Distinct NK Cell Function and Gene Expression in Children with Acute Lymphoblastic Leukemia in Remission Before and After Acute Exercise

ABSTRACT: Children and adolescents who have acute lymphoblastic leukemia (ALL), often display an impaired natural killer cell (NK) function. Brief bouts of exercise mobilize NK cells and influence their gene expression, but little is known about the effect of exercise on NK cell function and gene expression in pediatric ALL survivors, which remains unclear. This study examined the effect of exercise on NK gene expression and cytotoxic activity (NKCA) in pediatric ALL patients in remission. Nine B-cell ALL children in remission and 9 sex and age-matched healthy controls with no history of cancer (14.8±1 and 15±1 y/o, respectively; 2 girls per group) performed eight 2-min bouts of cycle ergometry at 60% of peak work rate (71±2% of V̇O 2 peak) interspersed with 1-min rest intervals. Circulating NK cells gene expression profile (RNA-seq) and NKCA (in vitro) were performed before and after exercise. NK cell function (NK cell cytotoxicity assay) and gene expression (RNAseq) analyses were performed. Exercise altered the expression of thousands of NK cell genes in both ALL and controls, with a distinct pattern in ALL both at baseline (294 Genes) and in response to exercise (179 genes). At baseline, nine gene pathways involved in NK cell function were affected, and following exercise, 28 pathways related to inflammatory response and cancer were impacted. NKCA was lower at baseline in survivors compared to controls. The reduced activity was partially mitigated following exercise but remained lower in ALL compared to controls. Exercise may improve NK cell function, specifically in immune surveillance in ALL children in remission, and has the potential to be used as adjunctive therapy in ALL. The differential gene expression response to exercise suggest that NK cells in ALL may adopt a different molecular strategy to fight infections or tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272928 | GEO | 2025/07/17

REPOSITORIES: GEO

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Project description:Many cancer survivors suffer from impairments in skeletal muscle (SkM), both in terms of reduced mass and function. Interestingly, human SkM possesses an epigenetic memory of earlier stimuli, such as exercise. Long-term retention of epigenetic changes in SkM following cancer survival and/or exercise training have not yet been studied. We therefore investigated genome-wide DNA methylation (the methylome) in SkM following a 5-month, 3/week treadmill-based aerobic training intervention in breast cancer survivors 10-14 years after diagnosis and treatment. These results were compared to breast cancer survivors who remained untrained and to age-matched controls with no history of cancer, who undertook the same training intervention. SkM biopsies were obtained before (pre) and after (post) the 5-month training period and DNA methylation was analysed using InfiniumEPIC 850K Arrays. The breast cancer survivors displayed a significant retention of increased DNA methylation (i.e., hypermethylation) at a larger number of differentially methylated positions (DMPs) compared with healthy age-matched controls pre-training. Training in cancer survivors led to an exaggerated number of DMPs with a hypermethylated signature occurring at more random non-regulatory regions across the DNA compared with training in healthy age-matched controls. However, the opposite occurred in important gene regulatory regions, where training in cancer survivors elicited a considerable reduction in methylation (i.e., hypomethylation) in 99% of the DMPs located specifically in CpG islands within promoter regions. Importantly, training was able to reverse the hypermethylation identified in cancer survivors back towards a hypomethylated signature that was observed pre-training in healthy age-matched controls at 300 (out of 881) of these island and promoter associated CpG sites. Pathway enrichment analysis identified that the training in cancer survivors evoked this predominantly hypomethylated signature in pathways associated with: Cell cycle, DNA replication and repair, transcription, translation, mTOR signalling and proteosome. Differentially methylated region (DMR) analysis also identified genes: BAG1, BTG2, CHP1, KIFC1, MKL2, MTR, PEX11B, POLD2, S100A6, SNORD104 and SPG7 as hypermethylated in breast cancer survivors with training reversing these CpG island / promoter associated DMRs towards a hypomethylated signature. Training also elicited a largely different epigenetic response in healthy individuals than that observed in cancer survivors, with very few overlapping changes. Only one gene, SIRT2, was identified as having altered methylation in cancer survivors at baseline as well as after training in both the cancer survivors and healthy controls. In conclusion, human SkM muscle retains a hypermethylated signature for as long as 10-14 years after breast cancer treatment and survival. Importantly, 5 months of aerobic training rejuvenated the SkM methylome towards signatures identified in healthy age-matched individuals in gene regulatory regions.

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Distinct NK Cell Function and Gene Expression in Children with Acute Lymphoblastic Leukemia in Remission Before and After Acute Exercise

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