Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver

Abundance and diversity of anammox bacteria in a mainstream municipal wastewater treatment plant

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Among the factors that obstruct the application of anammox-based technology for nitrogen removal from mainstream municipal wastewater is the water’s high organic loads. We hypothesized that some anammox species can adapt and grow in mainstream wastewater in which a minimal temperature of 13–15 °C is maintained. Using the AMX368F and AMX820R PCR-primers, anammox bacteria were detected in influent wastewater (COD/N ratio > 13) and in the anaerobic, anoxic, and aerobic chambers of a full-scale municipal wastewater treatment plant, reaching 107 copies/g VSS of the16S rRNA gene. Furthermore, anammox activity was demonstrated by 15N-isotopic tracing. The DNA sequences of clones randomly selected from a clone library were mainly clustered with Candidatus Brocadia flugida in addition to Ca. Brocadia sinica, Ca. Jettenia asiatica, and Ca. Anammoxoglobus propionicus. However, Ca. Brocadia was the only genus detected by high-throughput next-generation sequencing and denaturing gradient gel electrophoresis. The nitrite producers, ammonia-oxidizing archaea and bacteria, were both detected in the influent wastewater and the other chambers, while the nitrite consumers, Nitrospira nitrite oxidizers and the nirS-type denitrifiers, dominated all chambers. The results indicate the occurrence and potential activity of anammox bacteria in mainstream wastewater under certain conditions (proper temperature). The dominance of Brocadia flugida and Anammoxoglobus propionicus suggests a role for volatile fatty acids in selecting the anammox community in wastewater

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms.

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms.

Acknowledgements: We thank D. Bonnet, D. Passaro, A. Batsivari, H. Qian, L. Sandhow, R. C. Skoda, C. Nerlov, G. N. Enikolopov for the mouse models; N. Richoz and M. Clatworthy for access to intravital imaging; L. Arranz, C. L. F. de Castillejo, A. Rodríguez-Romera, C. Kapeni, E. Carrillo and other members of the S.M.-F group for assistance and discussions; A. Castillo Venzor, D. Pask, T. Hamilton (University of Cambridge) and the Central Biomedical Services & the Anne McLaren Building staff for support; and the Wellcome Trust-MRC Stem Cell Institute imaging core (D. Clements) and histopathology core (I. Pshenichnaya), the CIMR flow cytometry core (R. Schulte and G. Gondrys-Kotarba) and the Cambridge National Institute for Health and Care Research (NIHR) BRC Cell Phenotyping Hub for technical assistance. Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the Cambridge NIHR Biomedical Research Centre, Wellcome Trust-Medical Research Council (MRC) Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. A.H. gratefully acknowledges the support of the University of Cambridge Herchel Smith Fund through a Herchel Smith Postdoctoral Research Fellowship and the support of Darwin College Cambridge through a Research Fellowship. A.H. and B.D.S. also acknowledge the support of the core funding to the Wellcome/Cancer Research UK Gurdon Institute (nos. 203144/Z/16/Z and C6946/A24843). Work in the A.R.G. laboratory was supported by Wellcome (no. RG74909), WBH Foundation (no. RG91681), Alborada Trust (no. RG109433) and Cancer Research UK (no. RG83389). This work was supported by core support grants from the Wellcome Trust (no. 203151/Z/16/Z) and the MRC to the Cambridge Stem Cell Institute, Marie Skłodowska-Curie Career Action H2020-MSCA-IF-2015-708411 to C.K., National Health Institute Blood and Transplant (UK), Horizon 2020 ERC-2014-CoG-648765, MRC-AMED grant no. MR/V005421/1 and a Programme Foundation Award (no. C61367/A26670) from Cancer Research UK to S.M.-F. This research was funded in whole, or in part, by the Wellcome Trust (no. 203151/Z/16/Z) and the UK Research and Innovation MRC (no. MC_PC_17230). For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission.Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver