University of Cambridge > Talks.cam > Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer > Probing the rate limitation of a cancer driver mutation

Probing the rate limitation of a cancer driver mutation

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Csilla Kongsaysak-Lengyel1, Verena Körber2, Thorsten Feyerabend1, Thomas Höfer2 and Hans-Reimer Rodewald1.

1Division of Cellular Immunology, 2Division of Theoretical Systems Biology, German Cancer Research Center, D-69120 Heidelberg.

Cell competition between ‘young’ bone marrow-derived, and ‘old’ thymus-resident progenitors is a tumor suppressor mechanism in the thymus, preventing the development of T-cell acute lymphoblastic leukemia (T-ALL). Disruption of new influx of progenitors into the thymus provides a unique and robust system to unravel cellular and molecular events along the transition from normal T cell development to full blown T-ALLs, closely resembling the human disease. Because this model is independent of a priori introduced oncogenes, it makes the ‘natural emergence’ of clones and mutations kinetically accessible. Mutations in Notch1 are very prevalent in human T-ALLs. Notch1 gain-of-function mutations are most frequently frameshift mutations in the last Notch1 coding exon, leading via pre-mature stop codons to loss of the PEST domain and subsequent Notch protein stabilization. Csilla Kongsaysak-Lengyel and Thorsten Feyerabend generated a mutant mouse (Notch1Fsd) where these frameshift mutations are disabled to generate early stops. If driver mutations in Notch1 were rate-limiting for tumorigenesis, then Notch1Fsd mice should develop fewer tumors than control mice. Instead, Notch1Fsd mice develop tumors with the same incidence and kinetics, making use of alternative Notch1 mutations (direct stops) that are usually seen less frequently in control T-ALL. This implies that this DNA -mutation type, which is highly characteristic for this tumor, is not rate-limiting, since the cancer cells have an abundance of mutations to select from. Based on these leukemia experiments Verena Körber and Thomas Höfer modelled the impact of stem cell output on the risk of acquiring oncogenic drivers. Too high stem cell activity raises the probability of driver occurrence in stem cells whereas too low stem cell output fails to adequately renew progenitor clones and, hence, allows drivers to persist in progenitors. In line with this theoretical prediction, abrogating the renewal of T cell progenitors from hematopoietic stem cells in autonomous thymi causes multiple pre-leukemic clones to arise in the progenitors within weeks. Through subsequent rapid ‘tunneling’ of one or several further drivers, which are no longer rate-limiting (such as Notch frameshifts), a leukemic clone becomes selected. Our findings show how stem cell output and altered dwell times of progenitors shape oncogene activation and cancer development, and provide an experimental and theoretical framework to deconvolve the unfolding of this leukemia over time at high molecular and cellular resolution.

This talk is part of the Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer series.

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