Judith Zaugg, Caroline Pabst, Anthony D. Ho (emeritus group leader) and Carsten Müller-Tidow
Our research interest
Our research is focused on understanding the molecular and functional interactions between haematopoietic 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 leukaemic transformation.
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 characterised 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 leukaemic stem cells and the niche are likely to impact on disease initiation, maintenance and therapy response.
We are combining computational biology, multi-omics 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 leukaemia development.
Goals
Our research focuses on four major aspects of HSC–niche interactions:
- The role of ageing-related changes in stem cell–niche interactions in the development of haematological malignancies.
- Stem cell–niche communication in genetically defined AML subgroups.
- Role of RNA-modifications in stem cell biology and stem cell–niche interactions.
- The differential impact of distinct sources of donor HSCs on the recipient bone marrow niche.
Important publications
A Dynamic rRNA Ribomethylome Drives Stemness in Acute Myeloid Leukemia.
Zhou F, Aroua N, Liu Y, Rohde C, Cheng J, Wirth AK, Fijalkowska D, Göllner S, Lotze M, Yun H, Yu X, Pabst C, Sauer T, Oellerich T, Serve H, Röllig C, Bornhäuser M, Thiede C, Baldus C, Frye M, Raffel S, Krijgsveld J, Jeremias I, Beckmann R, Trumpp A, Müller-Tidow C.
Cancer Discov. 2023 Feb 6;13(2):332-347. doi: 10.1158/2159-8290.CD-22-0210.PMID: 36259929
Proteogenomics refines the molecular classification of chronic lymphocytic leukemia.
Herbst SA, Vesterlund M, Helmboldt AJ, Jafari R, Siavelis I, Stahl M, Schitter EC, Liebers N, Brinkmann BJ, Czernilofsky F, Roider T, Bruch PM, Iskar M, Kittai A, Huang Y, Lu J, Richter S, Mermelekas G, Umer HM, Knoll M, Kolb C, Lenze A, Cao X, Österholm C, Wahnschaffe L, Herling C, Scheinost S, Ganzinger M, Mansouri L, Kriegsmann K, Kriegsmann M, Anders S, Zapatka M, Del Poeta G, Zucchetto A, Bomben R, Gattei V, Dreger P, Woyach J, Herling M, Müller-Tidow C, Rosenquist R, Stilgenbauer S, Zenz T, Huber W, Tausch E, Lehtiö J, Dietrich S.
Nat Commun. 2022 Oct 20;13(1):6226. doi: 10.1038/s41467-022-33385-8.PMID: 36266272
Protein tyrosine kinase 2b inhibition reverts niche-associated resistance to tyrosine kinase inhibitors in AML.
Allert C, Waclawiczek A, Zimmermann SMN, Göllner S, Heid D, Janssen M, Renders S, Rohde C, Bauer M, Bruckmann M, Zinz R, Pauli C, Besenbeck B, Wickenhauser C, Trumpp A, Krijgsveld J, Müller-Tidow C, Blank MF.
Leukemia. 2022 Sep 2. doi: 10.1038/s41375-022-01687-x. Online ahead of print. PMID: 36056084
Behind-the-paper post: https://go.nature.com/3AKd0RF
Venetoclax synergizes with Gilteritinib in FLT3 wildtype high-risk Acute Myeloid Leukemia by suppressing MCL-1.
Janssen M, Schmidt C, Bruch PM, Blank MF, Rohde C, Waclawiczek A, Heid D, Renders S, Göllner S, Vierbaum L, Besenbeck B, Herbst SA, Knoll M, Kolb C, Przybylla A, Weidenauer K, Ludwig AK, Fabre MA, Gu M, Schlenk RF, Stölzel F, Bornhäuser M, Röllig C, Platzbecker U, Baldus CD, Serve H, Sauer T, Raffel S, Pabst C, Vassiliou GS, Vick B, Jeremias I, Trumpp A, Krijgsveld J, Müller-Tidow C, Dietrich S.
Blood. 2022 Jul 13:blood.2021014241. doi: 10.1182/blood.2021014241. Online ahead of print. PMID: 35857899
Glucose Metabolism and Aging of Hematopoietic Stem and Progenitor Cells.
Poisa-Beiro L, Landry JJM, Raffel S, Tanaka M, Zaugg J, Gavin AC, Ho AD.
Int J Mol Sci. 2022 Mar 11;23(6):3028. doi: 10.3390/ijms23063028.PMID: 35328449
CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia.
He L, Arnold C, Thoma J, Rohde C, Kholmatov M, Garg S, Hsiao CC, Viol L, Zhang K, Sun R, Schmidt C, Janssen M, MacRae T, Huber K, Thiede C, Hébert J, Sauvageau G, Spratte J, Fluhr H, Aust G, Müller-Tidow C, Niehrs C, Pereira G, Hamann J, Tanaka M, Zaugg JB, Pabst C.
EMBO Mol Med. 2022 Mar 7:e14990. doi: 10.15252/emmm.202114990. Online ahead of print. PMID: 35253392
Hotspot DNMT3A mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia sensitize cells to Azacytidine via viral mimicry response.
Scheller M, Ludwig A K, GöllnerS, RohdeC, KrämerS, StäbleS, Janssen M, Müller J-A, HeL, BäumerN, ArnoldC, Gerß J, Schönung M, ThiedeC, NiederwieserC, NiederwieserD, ServeH, BerdelW E, ThiemU, HemmerlingI, LeuschnerF, PlassC, Schlesner M, ZauggJ, MilsomM, TrumppA, PabstC, LipkaD B, Müller-TidowC.
Nature Cancer 2021, volume 2, pages 527–544 (2021).
Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics.
Velten L, Story BA, Hernández-Malmierca P, Raffel S, Leonce DR, Milbank J, Paulsen M, Demir A, Szu-Tu C, Frömel R, Lutz C, Nowak D, Jann JC, Pabst C, Boch T, Hofmann WK, Müller-Tidow C, Trumpp A, Haas S, Steinmetz LM.
Nat Commun. 2021 Mar 1;12(1):1366. doi: 10.1038/s41467-021-21650-1. PMID: 33649320
A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.
Wass M, Göllner S, Besenbeck B, Schlenk RF, Mundmann P, Göthert JR, Noppeney R, Schliemann C, Mikesch JH, Lenz G, Dugas M, Wermke M, Röllig C, Bornhäuser M, Serve H, Platzbecker U, Foerster KI, Burhenne J, Haefeli WE, Müller LP, Binder M, Pabst C, Müller-Tidow C; Study Alliance Leukemia (SAL).
Leukemia. 2020 Jun 19:1-11. doi: 10.1038/s41375-020-0892-z. Online ahead of print. PMID: 32561840
Site-specific methylation of 18S ribosomal RNA by SNORD42A is required for acute myeloid leukemia cell proliferation.
Pauli C, Liu Y, Rohde C, Cui C, Fijalkowska D, Gerloff D, Walter C, Krijgsveld J, Dugas M, Edemir B, Pabst C, Müller LP, Zhou F, Müller-Tidow C.
Blood. 2020 Jun 4;135(23):2059-2070. doi: 10.1182/blood.2019004121. PMID: 32097467
Glycogen accumulation, central carbon metabolism, and aging of hematopoietic stem and progenitor cells
Laura poisa‑Beiro, Judith Thoma, Jonathan Landry, Sven Sauer, Akihisa Yamamoto, Volker Eckstein, Natalie Romanov, Simon Raffel, Georg F. Hoffmann, Peer Bork, Vladimir Benes, Anne‑claude Gavin, Motomu Tanaka & Anthony D. Ho
Scientific Reports | (2020) 10:11597 | https://doi.org/10.1038/s41598-020-68396-2www.nature.com/scientificreports
Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML.
Garg S, Reyes-Palomares A, He L, Bergeron A, Lavallée VP, Lemieux S, Gendron P, Rohde C, Xia J, Jagdhane P, Müller-Tidow C, Lipka DB, Imren S, Humphries RK, Waskow C, Vick B, Jeremias I, Richard-Carpentier G, Hébert J, Sauvageau G, Zaugg J, Barabé F, Pabst C.
Blood. 2019 May 10. pii: blood.2018862383. doi: 10.1182/blood.2018862383. [Epub ahead of print]
PMID: 31076446
Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline.
Hennrich ML, Romanov N, Horn P, Jaeger S, Eckstein V, Steeples V, Ye F, Ding X, Poisa-Beiro L, Lai MC, Lang B, Boultwood J, Luft T, Zaugg JB, Pellagatti A, Bork P, Aloy P, Gavin AC, Ho AD.
Nat Commun. 2018 Oct 1;9(1):4004. doi: 10.1038/s41467-018-06353-4. PMID:30275468
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
