Dr Ingo Ringshausen
Haematopoietic stem cells and malignancies
Laboratory: Cambridge Stem Cell Institute, Clifford Albutt Building, Cambridge Biomedical Campus.
Departmental Affiliation: Haematology
Ingo Ringshausen studied medicine at the Johannes Gutenberg University in Mainz/ Germany and London/ Canada. After his graduation in 1999 he started his medical training in Internal Medicine and Haematology/ Oncology at the Technical University in Munich. Between 2003 and 2006 he joined the group of Gerard Evan at UCSF on a postdoctoral fellowship. After his board certification in 2010 he became a Consultant in the Department of Haematology/ Oncology in Munich and subsequently an independent group leader.
In 2014 he joined the Department of Haematology in Cambridge and is now appointed as Consultant Haematologist at Addenbrooke’s hospital and a Principal Investigator at the CSCI.
Cancer Research UK
Malignant B cells (green) actively remodel Bone marrow mesenchymal stromal cells (red)
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in western countries. Although CLL is a putative mature B cell malignancy, it has very recently been shown that the maturation of CD34+CD38- HSPC from CLL patients is skewed towards the lymphoid linage. Importantly, the majority of stem and progenitor cells from CLL patients carry disease specific mutations in NOTCH1, SF3B1, TP53 and XPO. These recent reports suggest that the initial oncogenic events can occur at the earliest stages of B cell specification in the stem cell compartment.
Our group previously demonstrated that malignant cells actively re-program mesenchymal stromal cells, a process that is dependent on the activation of NF-κB and essential for disease propagation. We are now interested in understanding how clonal evolution from a pre-malignant progenitor to a treatment-resistant B cell malignancy affects the activation and reprogramming of niche cells in the bone marrow microenvironment and how this contributes to microenvironment-mediated drug resistance. Related to this, we are investigating how the lymphoma-remodelled microenvironment impairs normal HSC biology, leading to bone marrow failure.
Jingyu Chen, Maurizio Mangolini, Andrew Moore, Eugene Park, Antonella Santoro, Vijitha Sathiaseelan
Similar to normal blood stem cells, malignant cells from patients with B cell lymphomas require signals from their surrounding environment for cell survival and proliferation. Thus, benign bystander cells provide crucial support for malignant cells, mediated by direct cell-cell contact and soluble factors. Understanding these cell-cell communications from a molecular viewpoint opens new directions to treat blood-born malignancies. Specifically, we want to understand: 1. How this cell-cell communication changes over time? Are malignant cells from patients with relapsed disease equally dependent on these signals? 2. How does this communication between malignant cells and their micro-environment affects the function of normal haematopoietic stem cells and the production of normal blood cells?
- Wagner M, Oelsner M, Moore A, Götte F, Kuhn PH, Haferlach T, Fiegl M, Bogner C, Baxter J, Peschel C, Follows GA, Ringshausen I (2015) Integration of innate- into adaptive- immune responses in ZAP-70 positive chronic lymphocytic leukaemia. Blood 2015 Oct 27. pii: blood-2015-05-646935. PMID:26508782
- Lutzny G, Kocher T, Rudelius M, Schmidt-Supprian M, Klein-Hitpass L, Finch A, Dürig J, Haferlach T, Seifert M, Wanninger S, Oostendorp R, Ruland J, Leitges M, Kuhnt T, Wagner M, Feuerstacke Y, Peschel C, Egle A, Ringshausen I. Proteinkinase C-β dependent activation of NF-κB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B-cells in vivo. Cancer Cell. 2013 Jan 14;23(1):77-92. PMCID:PMC3546417
- Ringshausen I, O'Shea CC, Finch AJ, Swigart LB, Evan GI. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell, 2006. 10(6): p. 501-14 PMID:17157790
- Christophorou MA, Ringshausen I, Finch AJ, Swigart LB, Evan GI The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature, 2006. 443(7108): p. 214-7. PMID:16957739
- Ringshausen I, Schneller F, Bogner C, Hipp S, Duyster J, Peschel C, Decker T. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta. Blood, 2002. 100(10): p. 3741-8. PMID:12393602