Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo.

BACKGROUND: Acute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells. METHODS: To identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR‒Cas9 pipeline in PDX models in vivo. RESULTS: A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo. CONCLUSIONS: These findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias.

Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress.

The cellular mechanisms required to ensure homeostasis of the hematopoietic niche and the ability of this niche to support hematopoiesis upon stress remain elusive. We here identify Wnt5a in Osterix+ mesenchymal progenitor and stem cells (MSPCs) as a critical factor for niche-dependent hematopoiesis. Mice lacking Wnt5a in MSPCs suffer from stress-related bone marrow (BM) failure and increased mortality. Niche cells devoid of Wnt5a show defective actin stress fiber orientation due to an elevated activity of the small GTPase CDC42. This results in incorrect positioning of autophagosomes and lysosomes, thus reducing autophagy and increasing oxidative stress. In MSPCs from patients from BM failure states which share features of peripheral cytopenia and hypocellular BM, we find similar defects in actin stress fiber orientation, reduced and incorrect colocalization of autophagosomes and lysosomes, and CDC42 activation. Strikingly, a short pharmacological intervention to attenuate elevated CDC42 activation in vivo in mice prevents defective actin-anchored autophagy in MSPCs, salvages hematopoiesis and protects against lethal cytopenia upon stress. In summary, our study identifies Wnt5a as a restriction factor for niche homeostasis by affecting CDC42-regulated actin stress-fiber orientation and autophagy upon stress. Our data further imply a critical role for autophagy in MSPCs for adequate support of hematopoiesis by the niche upon stress and in human diseases characterized by peripheral cytopenias and hypocellular BM.

Residing near allergenic trees can increase risk of allergies later in life: LISA Leipzig study.

BACKGROUND: We investigated whether residing in places with higher greenness, more trees and more allergenic trees early in life increases the risk of allergic outcomes, and whether these associations differ depending on the concentration of air pollutants. METHODS: The analytic sample included 631 children from the German birth cohort LISA Leipzig. Asthma and allergic rhinitis, sensitization to aeroallergens and food allergens, as well as confounders, were collected prospectively up to 15 years. Greenness was assessed by Normalized Difference Vegetation Index (NDVI). A tree registry was used to derive information on trees, which were classified into allergenic and non-allergenic. Annual average concentrations of nitrogen dioxide (NO2) and ozone were also used. Geographic exposures were assigned to home addresses at birth. Longitudinal associations were analysed using generalized estimating equations. RESULTS: Medium and high numbers (tertiles) of trees and allergenic trees in a 500 m buffer around birth addresses were associated with increased odds of allergic rhinitis up to 15 years regardless of NDVI. These exposures were also related to higher odds of sensitization to aeroallergens. Associations with asthma and sensitization to food allergens were less consistent. Effect estimates for allergic rhinitis were stronger in the high tertile of NO2 compared to the low tertile, while an opposite tendency was observed for ozone. CONCLUSION: We observed that early life residence in places with many trees, and allergenic trees specifically, may increase the prevalence of allergic rhinitis later in life. This association and its modification by air pollution should be pursued in further studies.