The molecular and cellular basis of B cell cancers in humans
Who: We invite motivated MSc candidates that would like to work in multidisciplinary teams to study the pathobiology of human B cell cancer in a very competitive life science lab.
What: We aim to advance the understanding and treatment of the disease group; current treatment involves high-costs severe side effects and high morbidity. We aim to define the way cells in the body promote and support B cell cancers; we will define the pathogenesis and perform drug sensitivity screens on patient cells.
Where: At the A-building Rikshospitalet, the Dept of Immunology – UiO, we are a Centre of Excellence (CIR) research group.
Background: B-cell malignancies account for 8% of cancer-related deaths; important subtypes such as chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and multiple myeloma (MM) are considered incurable with standard care. Recent advances have introduced 1) immunotherapy, where T cells are activated to kill cancer cells and 2) personalized medicine based on detailed molecular characterization of the tumors. This progress has led to Obama’s “moonshot to cure cancer”-initiative. However, many B-cell malignancies (with the notable exception of Hodgkin lymphoma (HL)) have shown low responsiveness to the new class of immunotherapy drugs called checkpoint inhibitors. Malignant B cells interact with T cells in ways that are very different from cancer cells from solid tumors, and in some cases, T cell subsets may help malignant B cells grow. Understanding the factors that determine the outcome of T cell recognition is required to design effective immunotherapy.Aims We aim to define the cellular and molecular basis of microenvironmental support of malignant B cells and thereby to propose a set of new targets for therapy. The master student will be a team member that will study either multiple myeloma, chronic lymphocytic leukemia or B-acute lymphoblastic leukemia. The master student can chose between at least three ongoing projects. In extension of this work, we are poised to test novel therapies in xenografted mice and in drug sensitivity screens for benefit of patients in Norway.
Vision Together with interdisciplinary partners we aim to continue to converge research as we have published in the very best general journals including two Nature papers this year (Nature 1,2, Nature Immunology3,4, Immunity5, Cell Reports6, JACI7, Leukemia8, J Exp Med9). Our collective goal is to enable highly competitive translational research, add research driven innovation, initiate new clinical trials and introduce frontline therapies that will benefit patients both nationally and internationally.
1 Khodadoust, M. S. et al. Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens. Nature, doi:10.1038/nature21433 (2017).
2 Chan, L. N. et al. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542, 479-483, doi:10.1038/nature21076 (2017).
3 Schjerven, H. et al. Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Nature immunology 14, 1073-1083, doi:10.1038/ni.2707 (2013).
4 Katerndahl, C. D. S. et al. Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nature immunology 18, 694-704, doi:10.1038/ni.3716 (2017).
5 Li, S. et al. Ikaros Inhibits Group 3 Innate Lymphoid Cell Development and Function by Suppressing the Aryl Hydrocarbon Receptor Pathway. Immunity 45, 185-197, doi:10.1016/j.immuni.2016.06.027 (2016).
6 Os, A. et al. Chronic lymphocytic leukemia cells are activated and proliferate in response to specific T helper cells. Cell reports 4, 566-577, doi:10.1016/j.celrep.2013.07.011 (2013).
7 Szodoray, P. et al. T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity. The Journal of allergy and clinical immunology 138, 839-851 e838, doi:10.1016/j.jaci.2016.01.035 (2016).
8 Wang, D. et al. Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in xenografted mice. Leukemia, doi:10.1038/leu.2017.69 (2017).
9 Schjerven, H. et al. Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre-B ALL. The Journal of experimental medicine, doi:10.1084/jem.20160049 (2017).