Dr Ingo Ringshausen
Haematopoeitic stem cells and malignancies
Cambridge Stem Cell Institute, Clifford Albutt Building, Cambridge Biomedical Campus
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.
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