Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas

Abstract

Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.

Mechanisms of NF-κB deregulation in lymphoid malignancies

“…Moreover, CK1␣ associates with CARD11 in ABC DLBCL and it was suggested to promote and terminate CBM signaling [83]. Recently, CK1␣ was also shown to recruit the ␤-Catenin destruction complex to active CARD11, leading to a stabilization of ␤-Catenin, which in turn cooperates with NF-B in the induction of distinct target genes in DLBCL cells [84]. Even though it is not yet clear in how far these different processes contribute to the potency of CARD11 mutations, the data indicate that CARD11 can connect to several oncogenic signaling networks to promote massive proliferation and survival in normal B-cells and B-cell lymphomas.…”

The CARD-CC/Bcl10/paracaspase signaling complex is functionally conserved since the last common ancestor of Planulozoa

“…Various PKC homologs can be found in a wide range of invertebrates (Kruse et al 1996) and are not correlating with the presence of the CBM complex, reflecting their importance in many alternative pathways. Analogously, the CBM-interacting proteins AIP (Schimmack et al 2014), caspase-8 (Kawadler et al 2008), β-catenin and its destruction complex (Bognar et al 2016), cIAP1/cIAP2 (Li, He, et al 2013) show poor conservation in invertebrates and might represent more recently evolved CBM interaction partners. Taken together, we can however conclude that the core CBM complex components seem to be evolutionary linked ( Figure 7A) and functionally interacting ever since the last common ancestor of the planulozoans.…”

“…Although the MALT1 scaffold function for recruitment of downstream TRAF6 has been clearly associated to NF-κB activation (Noels et al 2007), the MALT1 protease activity plays a more subtle role being specifically required for c-Rel activation (Ferch et al 2007;Gringhuis et al 2011;Hailfinger et al 2011;Baens et al 2014). There is some evidence that MALT1 also regulates or cross-talks with other pathways, such as JNK/AP-1 (Staal et al 2011), mTORC1 (Hamilton et al 2014), RhoA/ROCK (Klei et al 2016), MYC (Dai et al 2016) and possibly WNT (Bognar et al 2016). MALT1 belongs to the type 1 paracaspase family, which consists of an N-terminal death domain, immunoglobulin domains and a paracaspase domain (Hulpiau et al 2016).…”

“…), caspase-8(Kawadler et al 2008), β-catenin and its destruction complex(Bognar et al 2016), cIAP1/cIAP2), CK1α (Bidère et al 2009), CRADD (Lin et al 2012), CSN5 (Welteke et al 2009), MIB2 (Stempin et al 2011), NOTCH1 (Shin et al 2014), p62/SQSTM1 (Paul et al 2014), RLTPR (Roncagalli et al 2016) and Rubicon (Yang et al 2012) also show a wide phylogenetic distribution with no indications of a CBM co-evolution. In contrast, DEPDC7 (D'Andrea et al 2014), HECTD3 (Li, Chen, et al 2013), LRRK1 (Morimoto et al 2016) and Net1 (Vessichelli et al 2012) show a phylogenetic distribution or BLASTP ranking that correlates with presence of the CBM complex.…”

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

“…Despite the resistance of CARMA1 mutant DLBCL to BTK inhibitors, kinases like CK1α associate with oncogenic CARMA1 (Bidere et al, 2009;Bognar et al, 2016). Of note, even though deletion of the CARMA1 linker and CARMA1 CC mutations strongly induce NF-κB, only oncogenic mutants are leading to Ibrutinib resistance (Bognar et al, 2016).…”