Role of BCL10 somatic mutations in lymphomagenesis and response to BCR-targeted therapies

Role of BCL10 somatic mutations in lymphomagenesis and response to BCR-targeted therapies
ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a molecularly
heterogenous disease. Two recent genomic profiling studies of large DLBCL patient series subclassified these
patients in five distinct genomic groups. Both studies essentially agreed in their classification and described a
previously unnoticed subtype reminiscent of Marginal Zone Lymphoma (MZL), namely C1 or BN2 lymphoma.
This C1/BN2 subtype is characterized by frequent translocations of BCL6 and activating mutations of NOTCH2
and NF-κB signaling genes. Among the latter, 30% of the patients displayed BCL10 mutations, which are rare
in other DLBCL subtypes (<2%) but relatively common in MZL (8%). In fact, BCL10 is critical for MZ B-cell
development and its overexpression mediates hyperproliferation and eventually lymphomas of MZ origin.
However, the effect of BCL10 mutations on lymphomagenesis has not been studied.
BCL10 forms a high order complex (CBM) with CARD11 and MALT1, also lymphoma oncogenes. This complex
serves as a docking platform for recruitment and activation of other proteins leading to NF-κB activation. BCL10
somatic mutations in DLBCL can be classified in: CARD domain missense and C-terminus truncating mutants.
BCL10 CARD mediates CARD11-BCL10 and BCL10-BCL10 interactions while BCL10 C-terminal domain
mediates BCL10-MALT1 interaction. In preliminary studies, both classes of mutants accelerate BCL10
polymerization, rewire complex structure and composition and, induce constitutive activation of NF-κB mediated
transcription and MALT1 protease activity.
We hypothesize that CARD and C-terminal mutations induce gain-of-function and drive lymphomagenesis by
activating CBM complex activity and its downstream signaling pathways including NF-κB and that they will do
so through distinct molecular mechanisms. Based in our preliminary results, we predict that: i) BCL10 gain-of-
function mutations will enhance CBM complex activity by disrupting BCL10 auto-inhibitory structure through
distinct molecular mechanisms based on specific biochemical effects of CARD missense or C-terminal truncating
mutations; ii) this will cause acceleration of lymphomagenesis in cooperation with NOTHC2 activating mutations,
and iii) BCL10 gain-of-function mutations will confer resistance to classical BCR pathway kinase inhibitors such
as Ibrutinib (BTK inhibitor), thus requiring targeting downstream proteins such as MALT1 inhibitors or alternative
pathways.
Our goals for this proposal are to elucidate the molecular mechanism by which specific BCL10 somatic mutations
classes alter the high order molecular structure of the CBM complex, to determine how this impacts MZ B-cell
growth and survival to cause lymphomas, and to leverage this information to design of novel therapeutic
approaches for C1/BN2 lymphomas.

Grant Number: 5R01CA249843-05
NIH Institute/Center: NIH
Principal Investigator: Leandro Cerchietti