CARD11 and BCL2A1 Join Forces to Promote Resistance to Ibrutinib/Venetoclax Combination in Lymphoma Patients

Decombis, Salomé; Bellanger, Céline; Bris, Yannick Le; Boulet, Delphine; Jardine, Jane; Dousset, Christelle; Ménard, Audrey; Kervoëlen, Charlotte; Douillard, Elise; Minvielle, Stéphane; Moreau-Aubry, Agnès; Tessoulin, Benoît; Bidère, Nicolas; Gouill, Steven Le; Pellat‐Deceunynck, Catherine; Chiron, David

doi:10.1182/blood-2022-157694

Cited by 4 publications

(8 citation statements)

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“…CARD11 was the first CARD-CC family member where activating mutations were found, which cause spontaneous NF-κB activation and result in BENTA disease or B cell lymphoma [52]. Some of these activating mutations in CARD11 — for example CARD11 G123D [45,53], CARD11 L232LI [54,55], or CARD11 S250P [44] (Fig. 2B) — are mutated in residues that are conserved in several CARD-CC paralogs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

Staal

Driege

Gaever

et al. 2023

Preprint

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CARD9, -10, -11 and -14 all belong to the CARD-coiled coil (CC) protein family and originated from a single common ancestral protein early in vertebrate evolution. All four proteins form CARD-CC/BCL10/MALT1 (CBM) complexes leading to NF-kappaB activation after upstream phosphorylation by various protein kinase C (PKC) isoforms. CBM complex signaling is critical for innate and adaptive immunity, but aberrant activation can cause autoimmune or autoinflammatory diseases, or be oncogenic. CARD9 is the only family member that has retained the original domain organization. The other family members have been fused to a C-terminal ZO-1/Dlg5-like MAGUK domain, forming the CARMA sub-family. CARD9 shows a superior auto-inhibition with very low spontaneous activity when overexpressed in HEK293T cells. In contrast, the poor auto-inhibition of other CARD-CC family proteins, especially CARD10 (CARMA3) and CARD14 (CARMA2), is hampering characterization of upstream activators or activating mutations in overexpression studies. We grafted different domains from CARD10, -11 and 14 on CARD9 to generate chimeric Franken-CARD9 backbones for functional characterization of activating mutants using NF-κB reporter gene activation in HEK293T cells as readout. This revealed that most of the poor auto-inhibition of CARD10 and CARD14 can be mapped to the CARD10 LATCH and CARD14 CARD domains, respectively. CARD11 (CARMA1) activity was not further reduced by grafting on Franken-CARD9 backbones. The Franken-CARD9 approach was subsequently validated by using several known disease-associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several novel activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome-based disease association statistics, we found that activated alleles of CARD9 correlate with irritable bowel syndrome (IBS), constipation, arthritis, fibromyalgia, insomnia, anxiety and depression, which can occur as comorbidities.

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Section: Resultsmentioning

confidence: 99%

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

Staal

Driege

Gaever

et al. 2023

Preprint

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“…This combination can be considered a possible salvage therapy for ibrutinib-resistant MCL patients [ 165 ]. However, despite high initial response rates in the OAsIs trial nearly 1/3 of patients relapsed [ 166 ]. In order to identify factors leading to resistance in the OAsIs trial, single-cell RNA sequencing and targeted DNA sequencing of patients' tumor samples were performed ( n = 12 at baseline and n = 5 at relapse) that revealed a gain of function mutation in the CARD11 gene [ 166 ].…”

Section: Combination Approaches With Monoclonal Antibodies For the Tr...mentioning

confidence: 99%

“…However, despite high initial response rates in the OAsIs trial nearly 1/3 of patients relapsed [ 166 ]. In order to identify factors leading to resistance in the OAsIs trial, single-cell RNA sequencing and targeted DNA sequencing of patients' tumor samples were performed ( n = 12 at baseline and n = 5 at relapse) that revealed a gain of function mutation in the CARD11 gene [ 166 ]. Of note, while CARD11 mut tumor cells were minute (0.0005%) at the onset of treatment, all the cells carried a heterozygous mutation at the time of relapse.…”

Section: Combination Approaches With Monoclonal Antibodies For the Tr...mentioning

confidence: 99%

“…By integrating DNA sequencing data with single-cell RNA sequencing data, the authors identified the CARD11 associated gain of function mutation named "OAsIs-R" signature that was also predictive for OS/PFS in MCL patients treated with conventional chemotherapy. Furthermore, BCL2A1 overexpression was identified as the top gene of the OAsIs-R signature, which can be targetable by MALT1 protease inhibition along with BCL2 inhibition in a synergistic fashion [ 166 ].…”

Section: Combination Approaches With Monoclonal Antibodies For the Tr...mentioning

confidence: 99%

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Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

Jain,

Mamgain,

Chowdhury

et al. 2023

J Hematol Oncol

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Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2–6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton's tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody–drug conjugates.

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“…CARD11 was the first CARD-CC family member where activating mutations were found, which cause spontaneous NF-jB activation and result in BENTA disease or B cell lymphoma [53]. Some of these activating mutations in CARD11-for example CARD11 G123D [45,54], CARD11 L232LI [55,56], or CARD11 S250P [44] (Fig. 2B)-are mutated in residues that are conserved in several CARD-CC paralogs (Fig.…”

Section: Sequence Alignment Can Identify Activating Mutations Transfe...mentioning

confidence: 99%

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family

Staal,

Driege,

Van Gaever

et al. 2023

The FEBS Journal

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Caspase recruitment domain‐containing protein (CARD)9, CARD10, CARD11, and CARD14 all belong to the CARD‐coiled coil (CC) protein family and originated from a single common ancestral protein early in vertebrate evolution. All four proteins form CARD‐CC/BCL10/MALT1 (CBM) complexes leading to nuclear factor‐kappa‐B (NF‐κB) activation after upstream phosphorylation by various protein kinase C (PKC) isoforms. CBM complex signaling is critical for innate and adaptive immunity, but aberrant activation can cause autoimmune or autoinflammatory diseases, or be oncogenic. CARD9 shows a superior auto‐inhibition compared with other CARD‐CC family proteins, with very low spontaneous activity when overexpressed in HEK293T cells. In contrast, the poor auto‐inhibition of other CARD‐CC family proteins, especially CARD10 (CARMA3) and CARD14 (CARMA2), is hampering characterization of upstream activators or activating mutations in overexpression studies. We grafted different domains from CARD10, 11, and 14 on CARD9 to generate chimeric CARD9 backbones for functional characterization of activating mutants using NF‐κB reporter gene activation in HEK293T cells as readout. CARD11 (CARMA1) activity was not further reduced by grafting on CARD9 backbones. The chimeric CARD9 approach was subsequently validated by using several known disease‐associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several previously unknown activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome‐based disease association statistics, we found that activated alleles of CARD9 correlate with irritable bowel syndrome (IBS), constipation, osteoarthritis, fibromyalgia, insomnia, anxiety, and depression, which can occur as comorbidities.

show abstract

CARD11 and BCL2A1 Join Forces to Promote Resistance to Ibrutinib/Venetoclax Combination in Lymphoma Patients

Cited by 4 publications

References 0 publications

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family

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