Poster Presentation 25th Lorne Cancer Conference 2013

Investigating the effects of lymphoma mutations enhancing NFκB signalling (#220)

Yogesh Jeelall 1 , James Wang 1 , Chris Goodnow 1 2 , Keisuke Horikawa 1
  1. John Curtin School of Medical Research, ANU, Acton, ACT, Australia
  2. Australian Phenomics Facility, Canberra, ACT, Australia

NFκB signalling underlies the activation, multiplication and differentiation of B-lymphocytes. Recently, multiple mutations in the key signalling components of the NFκB pathway have been found in human B cell lymphomas. By retrovirally introducing individual gain-of-function CARD11 mutations present in diffuse large B cell lymphoma and a constitutively active version of IKBKB frequently found in cases of splenic marginal zone lymphoma into mouse B cells, we investigated whether or not B cell response is corrupted by single defined mutations in isolation from the >30 others present in malignant B cells. On their own, IKBKB and CARD11 mutations were sufficient to induce spontaneous growth of B cells in vitro. The extent of growth induction varied among the different mutations and correlated with strength of NFκB activation. Interestingly, when the same B cells were transferred into mice, mutant CARD11 expressing cells survived and expanded, whereas the cells expressing mutant IKBKB failed to survive, and were selectively “eliminated” from the recipients within 24 hours. Using genetic approaches, we found the elimination of mutant IKBKB expressing B cells was independent of both the BIM and FAS apoptotic pathways. We are currently testing whether the elimination of mutant IKBKB expressing B cells could potentially be mediated by other extrinsic factors. Our findings provide insights into changes in signalling and gene expression events immediately after acquisition of oncogenic mutations in normal activated B cells.