DNMT3A-R882 mutations intrinsically drive dysfunctional neutropoiesis from human haematopoietic stem cells
Mantica, G.; Vedi, A.; Tuval, A.; Huerga Encabo, H.; Hayler, D.; Krzywon, A.; Mitchell, E.; Dunn, W. G.; Biezuner, T.; Bastos, H. P.; Sham, K.; Santoro, A.; Lee, J.; Williams, N.; Danin, A.; Chapal, N.; Moskovitz, Y.; Arruda, A.; Fiorillo, E.; Orru, V.; Marongiu, M.; McKinney, E.; Cucca, F.; Collin, M.; Minden, M.; Campbell, P.; Vassiliou, G. S.; Fabre, M. A.; Nangalia, J.; Bonnet, D.; Shlush, L.; Laurenti, E.
Show abstract
Clonal haematopoiesis (CH) arises from the expansion of hematopoietic stem cells (HSCs) carrying leukaemia-associated somatic mutations. CH is linked to pathological immune dysregulation and a greater risk of age-related inflammatory diseases. Yet, how CH mutations impact HSC differentiation into immune effector cells remains understudied. Here, we report a single-cell resolution functional and multi-omic investigation of HSC clonal and differentiation dynamics in individuals with DNMT3A-R882 CH. DNMT3A-R882 reshapes the clonal architecture of haematopoiesis towards an aged phylogenetic structure. Functionally, DNMT3A-R882 HSCs produce decreased monocytic output but more abundant and mature neutrophil progeny compared to WT HSCs in the same individual. Whereas DNMT3A-R882 myeloid progenitors display attenuated inflammatory transcriptional programmes, DNMT3A- R882 mature neutrophils acquire proinflammatory and immunomodulatory features typical of maladaptive immunity and CH co-morbidities. Our findings, validated in humanised mice, identify aberrant DNMT3A-R882 HSC-driven neutropoiesis as a key link between CH, immune dysregulation and risk of inflammatory disease.
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