Porse Group: Stem cells in normal and malignant hematopoiesis
By working at the interface between normal and malignant hematopoiesis we will able to gain novel insights into both processes with the ambition to translate our findings for the benefit of future leukemia patients
Hematopoietic stem cells (HSCs) are residing at the apex of the hematopoietic differentiation hierarchy an are ultimately responsible for the life-long production of blood cells. Similarly, seminal work has demonstrated that leukemic stem cells (LSCs) are residing at the top of a parallel leukemic differentiation hierarchy, where they constantly fuel the production of leukemic blasts. The behaviour of both HSCs and LSCs are to a large extent controlled by gene regulatory networks which governs key stem cell fate options such as self-renewal, proliferation and differentiation. Our vision is that detailed mechanistic insights into the gene regulatory networks governing the behaviour of normal and malignant hematopoietic stem/progenitor cells (HSPCs) will uncover opportunities for translational approaches. Moreover, we strongly believe that analyses of these networks in both a normal and a leukemic context will synergize to forward our understanding of their function. Thus, to address our overall research vision, the overarching goals of our research are to:
- Understand the gene regulatory mechanisms that governs the behaviour of normal HSCs and myeloid lineage decision events during normal hematopoiesis
- Understand the gene regulatory mechanisms governing the behaviour of leukemic stem and progenitor cells
- To use the knowledge gained from 1) and 2) to identify novel potential targets for future treatment of leukaemia
By working at the interface between normal and malignant hematopoiesis we will able to gain novel insights into both processes with the ambition to translate our findings for the benefit of future AML patients.
Single cell analysis of HSC heterogeneity in pre-leukemic hematopoiesis.
Recent studies have shown that a substantial fraction (increasing with age) of healthy individuals carry oncogenic driver mutations in their blood cells involving genes such as DNMT3A, ASXL1 and TET2 – a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). At present we don´t know how these pre-leukemic HSCs from CHIP individuals are distinct from their normal counterparts and we´re currently studying this phenomenon by a variety of single cell approaches.
Identification of regulators of leukemic stem cells
Leukemic development, maintenance and relapse is fueled by a population of so-called leukemic stem cells (LSCs). Consequently, LSCs constitute ideal cellular targets for future therapeutic strategies. In order to identify, characterize and target novel LSC regulators we use a number of different strategies, including a combination of mouse models and phenotypic screens in vivo and in vitro.
Regulators of HSC self-renewal
Hematopoietic stem cells are the only cells able to sustain life-long hematopoiesis due to their ability to self-renew, thereby maintaining themselves, and to differentiate into all the cells of the blood stream. In contrast, multipotent progenitor cells, i.e. the downstream descendants of HSCs, have only limited self-renewal potential. The extent to which the loss of self-renewal is reversible is not known and we´re addressing this issue using a number of different approaches. Knowledge on how normal hematopoietic cells loose self-renewal properties may aid in our understanding of how leukemic cells re-acquire this property.
Lauridsen, F.K.B., Jensen, T.L., Rapin, N., Aslan, D., Wilhelmson, A.S., Pundhir, S., Rehn, M., Paul, F., Giladi, A., Hasemann, M.S., Serup, P., Amit, I., and Porse, B.T. (2018). Differences in Cell Cycle Status Underlie Transcriptional Heterogeneity in the HSC Compartment. Cell Reports 24, 766-780, doi:10.1016/j.celrep.2018.06.057.
Pundhir, S., Bratt Lauridsen, F.K., Schuster, M.B., Jakobsen, J.S., Ge, Y., Schoof, E.M., Rapin, N., Waage, J., Hasemann, M.S., and Porse, B.T. (2018). Enhancer and Transcription Factor Dynamics during Myeloid Differentiation Reveal an Early Differentiation Block in Cebpa null Progenitors. Cell Reports 23, 2744-2757, doi:10.1016/j.celrep.2018.05.012.
Knudsen, K.J., Rehn, M., Hasemann, M.S., Rapin, N., Bagger, F.O., Ohlsson, E., Willer, A., Frank, A.K., Sondergaard, E., Jendholm, J., Thoren, L., Lee, J., Rak, J., Theilgaard-Monch, K., and Porse, B.T. (2015). ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation. Genes and development 29, 1915-1929, doi:10.1101/gad.268409.115.
Willer, A., Jakobsen, J.S., Ohlsson, E., Rapin, N., Waage, J., Billing, M., Bullinger, L., Karlsson, S., and Porse, B.T. (2014). TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia. Leukemia 29, 1018-1031, doi:10.1038/leu.2014.307.
Rapin, N., Bagger, F.O., Jendholm, J., Mora-Jensen, H., Krogh, A., Kohlmann, A., Thiede, C., Borregaard, N., Bullinger, L., Winther, O., Theilgaard-Monch, K., and Porse, B.T. (2014). Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients. Blood 123, 894-904, doi:10.1182/blood-2013-02-485771.
Ohlsson, E., Schuster, M.B., Hasemann, M., and Porse, B.T. (2016). The multifaceted functions of C/EBPalpha in normal and malignant haematopoiesis. Leukemia 30, 767-775, doi:10.1038/leu.2015.324.
Hasemann, M.S., Lauridsen, F.K., Waage, J., Jakobsen, J.S., Frank, A.K., Schuster, M.B., Rapin, N., Bagger, F.O., Hoppe, P.S., Schroeder, T., and Porse, B.T. (2014). C/EBPalpha is required for long-term self-renewal and lineage priming of hematopoietic stem cells and for the maintenance of epigenetic configurations in multipotent progenitors. PLoS Genet 10, e1004079, doi:10.1371/journal.pgen.1004079.