Quantitative analysis of redox proteome reveals oxidation-sensitive protein thiols acting in fundamental processes of developmental hematopoiesis

Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behavior in normal and malignant hematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4,438 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenic changes to oxidation state of thiols in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified oxidation changes to thiols acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signaling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redoxsensitive proteins in in utero-initiated MLL-rearranged leukemia.

Automated summary

Fetal and adult hematopoietic stem and progenitor cells have distinct redox homeostasis, with fetal cells being more susceptible to protein thiol oxidation. The study reveals ontogenic changes to oxidation state of thiols in proteins involved in metabolism and protein homeostasis, as well as thiol oxidation changes in mitochondrial respiration and protein homeostasis during initiation of MLL-rearranged leukemia in fetal hematopoietic stem and progenitor cells.