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

Award Number: R01CA249843
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $531,919 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	000	5	7/1/2024	NON-COMPETING CONTINUATION	$531,919
														Subtotal = $531,919

Issue Date FY: 2023 ( Subtotal = $545,957 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	4	6/29/2023	NON-COMPETING CONTINUATION	$545,957
														Subtotal = $545,957

Issue Date FY: 2022 ( Subtotal = $548,714 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	3	7/5/2022	NON-COMPETING CONTINUATION	$548,714
														Subtotal = $548,714

Issue Date FY: 2021 ( Subtotal = $557,099 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	2	6/23/2021	NON-COMPETING CONTINUATION	$557,099
														Subtotal = $557,099

Issue Date FY: 2020 ( Subtotal = $567,442 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	1	9/4/2020	NEW	$0
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	5/29/2020	NEW	$567,442
														Subtotal = $567,442

Grand Total All Awards = $2,751,131

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

Award Number: R01CA249843

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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