Ragnar Söderbergforskare i medicin // År: 2014 //
Anslagsförvaltare: Lunds Universitet // Belopp: 8 000 000 kr
Blodcellsproduktion innebär att en variation av celler med olika funktion utvecklas från ett litet antal blodstamceller i benmärgen. Denna egenskap utnyttjas i benmärgstransplantationer där endast stamcellerna kan återuppbygga ett förlorat blodsystem.
Precis som i det normala blodsystemet så är det några få leukemiska stamceller som står för produktionen av alla cancerceller i en leukemi och som självförnyas så att denna produktion bibehålls. Det är också de leukemiska stamcellerna som är ansvariga för metastaser och återfall efter behandling. För att bota svårbehandlad leukemi är det således viktigt att på ett effektivt och specifikt sätt kunna slå ut de leukemiska stamcellerna. Ett problem är att normala och leukemiska stamceller är mycket lika till utseendet och svåra att separera trots att de skiljer sig väsentligt i funktion och molekylär sammansättning från normala stamceller.
Forskningsprojektets målsättning är att använda varje cells unika molekylära sammansättning för att hitta specifika cellmarkörer för olika blod- och leukemistamceller. Detta skulle göra det möjligt att separera dem och studera hur de regleras och på så sätt identifiera vilka faktorer som är viktiga vid leukemi. Våra resultat ska bana väg för nya behandlingsmetoder som på ett specifikt sätt ska kunna slå ut leukemiska stamceller. På det här viset skulle också de patienter som drabbats av de svåraste formerna av leukemi kunna botas.
Hematopoiesis is maintained by a small number of hematopoietic stem cells (HSCs) that have the capacity to differentiate into all hematopoietic lineages, and at the same time self-renew to maintain the HSC pool. These properties can be measured through transplantation assays where only true HSCs give life-long multilineage reconstitution of the blood system. Consequently, HSCs are essential for maintaining hematopoietic homeostasis and have substantial clinical relevance as the critical cellular component of stem cell transplantations in cell- or gene therapy protocols for treatment of hematological disorders. Hematopoiesis is also the conceptual paradigm against which all stem cell systems are compared, largely because of the ability to isolate and characterize distinct hematopoietic cell fractions.
The ability to purify distinct hematopoietic cell fractions has afforded the prospective isolation of a range of hematopoietic progenitors, thus providing detailed descriptions of the hierarchical organization of the hematopoietic system as well as of the transcriptional programs regulating commitment steps. However, prospective isolation of hematopoietic cell fractions is an ongoing process of refinement, and within populations currently defined as HSCs, subclasses of cells with variable reconstitution kinetics, lineage output, and self-renewal potential have been defined. We have developed strategies to delineate the cellular heterogeneity of HSC-containing fractions. This is particularly critical for molecular characterization of HSCs and their progeny as transcriptional programs from functionally different cells are otherwise confounded.
Accumulating evidence describes malignant disease as having features similar to normal tissue organization, hierarchically structured with the tumor-driving cancer stem cells at its apex. Accordingly, leukemia is organized in cellular hierarchies where the leukemic stem cells (LSCs) drive the tumor growth. LSCs have stem cell characteristics such as self-renewal capacity, quiescence and drug resistance, causing metastasis and relapse. They are therefore a critical priority as targets for therapy. In close collaboration with hematology clinics throughout Europe we focus on identifying and targeting therapy resistant LSCs in different myeloid leukemias.
1. S Singbrant, M Wall, J Moody, G Karlsson, AM Chalk, B Liddicoat, MR Russell, CR Walkley, S Karlsson (2014). The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease. Haematologica 99(4):647- 655.
2. G May, S Soneji, AJ Tipping, J Teles, SJ McGowan, M Wu, Y Guo, C Fugazza, J Brown, G Karlsson, C Pina, V Olariu, S Taylor, DG Tenen, C Peterson, T Enver (2013). Dynamic analysis of gene expression and genome wide transcription factor binding during lineagespecification of multipotent progenitors. Cell Stem Cell 13(6):754-68.
3. G Karlsson, E Rorby, C Pina, S Soneji, K Reckzeh, Y Guo, K Miharada, C Karlsson, C Fugazza, R Gupta, J Marten, H Stunnenberg, S Karlsson, T Enver (2013). The tetraspanin CD9 affords high purity capture of all murine hematopoietic stem cells. Cell Reports 29;4(4):642-8.
4. C Karlsson, A Baudet, N Miharada, S Soneji, R Gupta, M Magnusson, T Enver, G Karlsson, J Larsson (2013). Identification of the chemokine CCL28 as a growth and survival factor for human hematopoietic stem- and progenitor cells. Blood 121(19):3838-42.
5. E Rörby, M Nifelt Hagerstrom, U Blank, *G Karlsson, *S Karlsson (2012). Human hematopoietic stem/progenitor cells overexpressing Smad4 exhibit impaired reconstitution potential in vivo. Blood 120(22):4343-51.
6. K Siva, P Jaako, K Miharada, E Rörby, M Ehinger, G Karlsson, S Karlsson (2012). SPARC is dispensable for murine hematopoiesis, despite its suspected pathophysiological role in 5qmyelodysplastic syndrome. Leukemia 26(11):2416-9.
7. S Yamazaki, H Ema, G Karlsson, T Yamaguchi, S Shioda, M Taketo, S Karlsson, A Iwama, H Nakauchi (2011). Nonmyelinating schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147(5):1146-58.
8. K Miharada, G Karlsson, M Rehn, E Rorby, K Siva, J Cammenga, and S Karlsson (2011). Cripto regulates hematopoietic stem cells as a hypoxic niche related factor through cell surface receptor GRP78. Cell Stem Cell 9(4);330-44.
9. R Quéré, G Karlsson, F Hertwig, M Rissler, B Lindqvist, K Reckzeh, T Fioretos, ML Slovak, FN Khac, P Vandenberghe, J Cammenga and S Karlsson (2011). SMAD4 binds HOXA9 in the cytoplasm and protects primitive hematopoietic cells against nuclear activation by HOXA9 and leukemia transformation. Blood 2;117(22):5918-30.
10. R Quéré, S Andradottir, Ann Brun, G Karlsson, M Magnusson, K Olsson, RA Zubarev, J Cammenga and S Karlsson. (2011). High levels of the adhesion molecule CD44 on leukemic cells generate acute myeloid leukemia relapse after withdrawal of the initial transforming event. Leukemia 25(3):515-26.
* Corresponding authors
In November 2012 I decided to start applying for independent grants to form my own research group. In October 2014 I hired my first PhD student and was appointed Ragnar Söderberg Fellow in Medicine
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