Epidermal growth factor receptor–dependent DNA repair promotes murine and human hematopoietic regeneration

Abstract

Chemotherapy and irradiation cause DNA damage to hematopoietic stem cells (HSCs), leading to HSC depletion and dysfunction and risk for malignant transformation over time. Extrinsic regulation of HSC DNA repair is not well understood and therapies to augment HSC DNA repair following myelosuppression remain undeveloped. We report that epidermal growth factor receptor (EGFR) regulates DNA repair in HSCs following irradiation via activation of the DNA-dependent protein kinase - catalytic subunit (DNA-PKcs) and nonhomologous end joining (NHEJ). We show that hematopoietic regeneration in vivo following total body irradiation (TBI) is dependent upon EGF - mediated repair of DNA damage via activation of DNA-PKcs. Conditional deletion of EGFR in hematopoietic stem/progenitor cells (HSPCs) significantly decreased DNA-PKcs activity following irradiation, causing increased HSC DNA damage and depressed HSC recovery over time. Systemic administration of EGF promoted HSC DNA repair and rapid hematologic recovery in chemotherapy - treated mice and had no effect on AML growth in vivo. Further, EGF treatment drove the recovery of human HSCs capable of multilineage in vivo repopulation following radiation injury. Whole genome sequence analysis revealed no increase in coding region mutations in HSPCs from EGF - treated mice, but increased intergenic copy number variant mutations were detected. These studies demonstrate that EGF promotes HSC DNA repair and hematopoietic regeneration in vivo via augmentation of NHEJ. EGF has therapeutic potential to promote human hematopoietic regeneration and further studies are warranted to assess long-term hematopoietic effects.

RPRM deletion preserves hematopoietic regeneration by promoting EGFR‐dependent DNA repair and hematopoietic stem cell proliferation post ionizing radiation

“…Although it is still unclear how RPRM regulated the expression of EGFR and its phosphorylation, which needs further study, these results are in agreement with a recent report that EGFR regulates DNA repair in HSCs following irradiation via activation of DNA-PKcs (Fang et al, 2020). Interestingly, our results also suggested that EGFR Our study also suggests that RPRM deletion promotes HSC survival through the EGFR-STAT3-Lin28a pathway.…”

“…In addition to promoting DNA‐PKcs activation and increasing Xrcc6 expression, our study suggested that RPRM deletion increased the expression levels of EGFR and p‐EGFR in irradiated HSCs. Although it is still unclear how RPRM regulated the expression of EGFR and its phosphorylation, which needs further study, these results are in agreement with a recent report that EGFR regulates DNA repair in HSCs following irradiation via activation of DNA‐PKcs (Fang et al, 2020 ). Interestingly, our results also suggested that EGFR and DNA‐PKcs formed a feedback loop to regulate DNA repair since inhibiting DNA‐PKcs activation could significantly downregulate the expression of EGFR and p‐EGFR confirming the reciprocal relationship between DNA‐PKc phosphorylation and EGFR‐mediated radiation response (Javvadi et al, 2012 ).…”

Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival

“…7F). EGF signaling has also been implicated in maintaining genomic integrity in hematopoietic stem cells (48). We therefore assessed γ-H2AX levels in inducible…”

A narrative review on Epidermal Growth Factor (EGF) intralesional infiltrations for diabetic complex wounds: The rational of an innovative delivery route

“…Likewise, EGF showed to activate the expression of human telomerase reverse transcriptase in cultured cells, via Ets-2, a cancerspecific transcription factor that appears to depend on EGF receptor (EGFR)-mediated Erk and Akt activation [115]. Experimental studies suggest that EGF enhances cell survival and tissue replenishment in otherwise lethal scenarios, by controlling oxidative stress and by mitigating cellular senescence [116][117][118][119].…”