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SUMMARY:Probing the rate limitation of a cancer driver mutation - Hans-Rei
 mer Rodewald\, DKFZ
DTSTART:20221013T120000Z
DTEND:20221013T130000Z
UID:TALK165715@talks.cam.ac.uk
CONTACT:Kate Davenport
DESCRIPTION:Csilla Kongsaysak-Lengyel1\, Verena Körber2\, Thorsten Feyera
 bend1\, Thomas Höfer2 and Hans-Reimer Rodewald1. \n\n1Division of Cellula
 r Immunology\, 2Division of Theoretical Systems Biology\, German Cancer Re
 search Center\, D-69120 Heidelberg.\n\nCell competition between 'young' bo
 ne marrow-derived\, and 'old' thymus-resident progenitors is a tumor suppr
 essor mechanism in the thymus\, preventing the development of T-cell acute
  lymphoblastic leukemia (T-ALL). Disruption of new influx of progenitors i
 nto the thymus provides a unique and robust system to unravel cellular and
  molecular events along the transition from normal T cell development to f
 ull blown T-ALLs\, closely resembling the human disease. Because this mode
 l is independent of a priori introduced oncogenes\, it makes the 'natural 
 emergence' of clones and mutations kinetically accessible. Mutations in No
 tch1 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 subsequ
 ent Notch protein stabilization. Csilla Kongsaysak-Lengyel and Thorsten Fe
 yerabend generated a mutant mouse (Notch1Fsd) where these frameshift mutat
 ions are disabled to generate early stops. If driver mutations in Notch1 w
 ere rate-limiting for tumorigenesis\, then Notch1Fsd mice should develop f
 ewer tumors than control mice. Instead\, Notch1Fsd mice develop tumors wit
 h the same incidence and kinetics\, making use of alternative Notch1 mutat
 ions (direct stops) that are usually seen less frequently in control T-ALL
 . This implies that this DNA-mutation type\, which is highly characteristi
 c for this tumor\, is not rate-limiting\, since the cancer cells have an a
 bundance of mutations to select from. Based on these leukemia experiments 
 Verena Körber and Thomas Höfer modelled the impact of stem cell output o
 n the risk of acquiring oncogenic drivers. Too high stem cell activity rai
 ses the probability of driver occurrence in stem cells whereas too low ste
 m cell output fails to adequately renew progenitor clones and\, hence\, al
 lows drivers to persist in progenitors. In line with this theoretical pred
 iction\, abrogating the renewal of T cell progenitors from hematopoietic s
 tem 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 (su
 ch as Notch frameshifts)\, a leukemic clone becomes selected. Our findings
  show how stem cell output and altered dwell times of progenitors shape on
 cogene activation and cancer development\, and provide an experimental and
  theoretical framework to deconvolve the unfolding of this leukemia over t
 ime at high molecular and cellular resolution.\n
LOCATION:CRUK CI Lecture Theatre
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