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Molecular Medicine Partnership Unit

 

Stem Cell–Niche Networks in Ageing and Disease

Judith Zaugg, Anthony D. Ho, Carsten Müller-Tidow, Anne-Claude Gavin and Caroline Pabst
Judith Zaugg, Anthony D. Ho, Carsten Müller-Tidow, Anne-Claude Gavin and Caroline Pabst

Caroline Pabst, Carsten Müller–Tidow, Anthony D. Ho (emeritus group leader) and Anne–Claude Gavin, Judith Zaugg

Our research interest

Our research is focused on understanding the molecular and functional interactions between hematopoietic stem cells (HSCs) and the bone marrow niche. We primarily use the most plastic niche cell population, mesenchymal stroma cells (MSCs), to model HSC - stroma cell interactions in vitro. We are specifically interested in understanding the role of MSCs in acute myeloid leukaemia (AML), and how changes in HSC-niche interactions during ageing might contribute to leukemic transformation.

We are combining computational biology, multiomics methods, co-culture systems of primary human cells, and xenotransplantations to study the mutual impact of the different cell types on each other during ageing and leukemia development.

 

Background

Bone marrow harbours different types of stem cells comprising HSCs, which give rise to all blood cells, and MSCs, which can differentiate into different stroma cell types. MSCs play a pivotal role in maintaining normal HSC functions such as survival, quiescence, proliferation and differentiation.

Our previous work has focused on understanding the pathogenesis of AML. AML is characterized by a rather small number of disease inducing mutations and multiple epigenetic changes. Results from our groups and others point towards the niche as an essential player in AML pathogenesis. Interactions between leukemic stem cells and the niche are likely to impact on disease initiation, maintenance and therapy response.

Goals

Our research focuses on three major aspects of HSC - niche interactions:

  1. Role of ageing-related changes in stem cell- niche interactions in the development of haematological malignancies
  2. Stem cell - niche communication in genetically defined AML subgroups.
  3. The differential impact of distinct sources of donor HSCs on the recipient bone marrow niche

 

Important publications

AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia. Zhou F, Liu Y, Rohde C, Pauli C, Gerloff D, Köhn M, Misiak D, Bäumer N, Cui C, Göllner S, Oellerich T, Serve H, Garcia-Cuellar MP, Slany R, Maciejewski JP, Przychodzen B, Seliger B, Klein HU, Bartenhagen C, Berdel WE, Dugas M, Taketo MM, Farouq D, Schwartz S, Regev A, Hébert J, Sauvageau G, Pabst C, Hüttelmaier S, Müller-Tidow C.
Nat Cell Biol. 2017 Jul;19(7):844-855. doi: 10.1038/ncb3563. Epub 2017 Jun 26. PMID:28650479

 

Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia.
Göllner S, Oellerich T, Agrawal-Singh S, Schenk T, Klein HU, Rohde C, Pabst C, Sauer T, Lerdrup M, Tavor S, Stölzel F, Herold S, Ehninger G, Köhler G, Pan KT, Urlaub H, Serve H, Dugas M, Spiekermann K, Vick B, Jeremias I, Berdel WE, Hansen K, Zelent A, Wickenhauser C, Müller LP, Thiede C, Müller-Tidow C.
Nat Med. 2017 Jan;23(1):69-78. doi: 10.1038/nm.4247. Epub 2016 Dec 12. PMID: 27941792

 

GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo.
Pabst C
, Bergeron A, Lavallée VP, Yeh J, Gendron P, Norddahl GL, Krosl J, Boivin I, Deneault E, Simard J, Imren S, Boucher G, Eppert K, Herold T, Bohlander SK, Humphries K, Lemieux S, Hébert J, Sauvageau G, Barabé F.
Blood. 2016 Apr 21;127(16):2018-27. doi: 10.1182/blood-2015-11-683649. Epub 2016 Feb 1. PMID: 26834243

 

 

SNPhood: investigate, quantify and visualise the epigenomic neighbourhood of SNPs using NGS data. Arnold C, Bhat P, Zaugg JB.
Bioinformatics. 2016 Aug 1;32(15):2359-60. doi: 10.1093/bioinformatics/btw127. Epub 2016 Mar 26. PMID:27153574

 

Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions. Grubert F, Zaugg JB, Kasowski M, Ursu O, Spacek DV, Martin AR, Greenside P, Srivas R, Phanstiel DH, Pekowska A, Heidari N, Euskirchen G, Huber W, Pritchard JK, Bustamante CD, Steinmetz LM, Kundaje A, Snyder M.
Cell. 2015 Aug 27;162(5):1051-65. doi: 10.1016/j.cell.2015.07.048.
Epub 2015 Aug 20. PMID: 26300125

 

Identification of small molecules that support human leukemia stem cell activity ex vivo.
Pabst C
, Krosl J, Fares I, Boucher G, Ruel R, Marinier A, Lemieux S, Hébert J, Sauvageau G.
Nat Methods. 2014 Apr;11(4):436-42. doi: 10.1038/nmeth.2847. Epub 2014 Feb 23. PMID: 24562423

 

Research group's MMPU link to EMBL web page

 

 

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