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Lymphomagenic CARD11/BCL10/MALT1 Signaling Drives Malignant B-Cell Proliferation Via Cooperative NF-Κb and JNK Activation

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Lymphomagenic CARD11/BCL10/MALT1 Signaling Drives Malignant B-Cell Proliferation Via Cooperative NF-Κb and JNK Activation Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation Nathalie Kniesa, Begüm Alankusa, Andre Weilemannb,c, Alexandar Tzankovd, Kristina Brunnera, Tanja Ruffa, Marcus Kremere, Ulrich B. Kellerf, Georg Lenzb,c, and Jürgen Rulanda,g,h,1 aInstitut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany; bTranslational Oncology, Department of Medicine A, University Hospital Münster, 48149 Münster, Germany; cCells in Motion, Cluster of Excellence EXC 1003, 48149 Münster, Germany; dInstitute of Pathology, University Hospital Basel, 4031 Basel, Switzerland; eInstitut für Pathologie, Klinikum Harlaching, 81545 Munich, Germany; fDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany; gGerman Cancer Consortium, 69120 Heidelberg, Germany; and hGerman Center for Infection Research, 81675 München, Germany Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, and approved November 12, 2015 (received for review April 16, 2015) The aggressive activated B cell-like subtype of diffuse large B-cell (PI3K) (reviewed in ref. 8). The key link to the IKK complex is lymphoma is characterized by aberrant B-cell receptor (BCR) signal- the scaffolding molecule caspase recruitment domain-containing ing and constitutive nuclear factor kappa-B (NF-κB) activation, which protein 11 (CARD11), which is inactive in resting cells due to an is required for tumor cell survival. BCR-induced NF-κBactivationre- intramolecular inhibitory interaction between its linker region quires caspase recruitment domain-containing protein 11 (CARD11), and its coiled-coil domain (9). B-cell activation induces PKCβ- and CARD11 gain-of-function mutations are recurrently detected in mediated phosphorylation of CARD11, which relieves the pro- human diffuse large B-cell lymphoma (DLBCL). To investigate the con- tein from autoinhibition, resulting in recruitment of the adapter sequences of dysregulated CARD11 signaling in vivo, we generated protein B-cell CLL/lymphoma 10 (BCL10) and paracaspase mu- mice that conditionally express the human DLBCL-derived CARD11 cosa-associated lymphoid tissue lymphoma translocation gene 1 (L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger (MALT1), and the formation of the CARD11/BCL10/MALT1 aggressive B-cell lymphoproliferation, leading to early postnatal (CBM) complex. Further recruitment of activating factors such lethality. CARD11(L225LI) constitutively associated with B-cell CLL/ as TRAF proteins and casein kinase 1 α (CK1α), as well as IKKs lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lym- and TAK1, leads to IKK and c-Jun N-terminal kinase (JNK) phoma translocation gene 1 (MALT1) to simultaneously activate the activation (10, 11). NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic RNA interference screens have revealed that CARD11, BCL10, deficiencies of either BCL10 or MALT1 completely rescued the phe- and MALT1 are all essential for survival of ABC-DLBCL cells, notype, and pharmacological inhibition of JNK was, similar to NF-κB consistent with the key role of the CBM complex in NF-κBacti- blockage, toxic to autonomously proliferating CARD11(L225LI)- vation (12). Moreover, a series of gain-of-function mutations that expressing B cells. Moreover, constitutive JNK activity was observed disrupt the autoinhibitory mechanism were identified in the coiled- in primary human activated B cell-like (ABC)-DLBCL specimens, and coil domain of CARD11 in human DLBCL (13). Regardless, the human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/ Significance MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC- The activated B cell-like (ABC) subtype of diffuse large B-cell DLBCL. lymphoma (DLBCL) has a poor clinical outcome and is charac- terized by constitutive caspase recruitment domain-containing diffuse large B-cell lymphoma | CARD11 | NF-κB | JNK | mouse model protein 11 (CARD11)/B-cell CLL/lymphoma 10 (BCL10)/mucosa- associated lymphoid tissue lymphoma translocation gene 1 iffuse large B-cell lymphoma (DLBCL) is the most frequent (MALT1) signaling and nuclear factor kappa-B (NF-κB) activation, Dlymphoma in adults. It is an aggressive disease that com- which is essential for tumor cell survival. However, NF-κBin- prises several subsets, including the activated B cell-like (ABC) hibitors have not reached the clinic due to high toxicity, and and germinal-center B cell-like (GCB) subtypes (1); the ABC alternative strategies for targeted therapies are needed. Using subset in particular is characterized by poor survival (2). ABC- mouse genetics, we demonstrate that forced CARD11/BCL10/ DLBCL cells exhibit gene expression signatures similar to normal MALT1 signaling drives lethal lymphoproliferation through si- B cells activated by B-cell receptor (BCR) engagement and a multaneous NF-κB and c-Jun N-terminal kinase (JNK) activation. constitutive activation of the canonical nuclear factor kappa-B Pharmacological inhibition of JNK was similar to NF-κB blockage (NF-κB) pathway, which is essential for survival of the tumor cells and toxic to autonomously proliferating murine B cells, and (3, 4). Canonical NF-κB signaling is regulated by IκB kinase β constitutive JNK activity was observed in human ABC-DLBCL (IKKβ), which induces proteolytic degradation of inhibitory IκB cells, which are also sensitive to JNK inhibitors. Our results proteins by their phosphorylation and thereby allows translocation identify the JNK pathway as a therapeutic target for DLBCL. κ of NF- B transcription factors into the nucleus. Although small Author contributions: N.K., A.W., and J.R. designed research; N.K., B.A., A.W., K.B., and T.R. molecule inhibitors of IKKβ efficiently block the growth of ABC- performed research; N.K., A.W., A.T., M.K., U.B.K., G.L., and J.R. analyzed data; and N.K. DLBCL cells in vitro (5), clinical trials failed due to highly toxic side and J.R. wrote the paper. effects (NCT00003979) (6, 7). The authors declare no conflict of interest. Physiological NF-κB activation by the BCR is initiated by This article is a PNAS Direct Submission. receptor-proximal tyrosine kinases, such as spleen tyrosine ki- Freely available online through the PNAS open access option. nase (SYK) and Bruton agammaglobulinemia tyrosine kinase 1To whom correspondence should be addressed. Email: [email protected]. (BTK), which trigger activation of downstream modules, including This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. protein kinase C, beta-1 (PKCβ) and phosphatidylinositol 3-kinase 1073/pnas.1507459112/-/DCSupplemental. E7230–E7238 | PNAS | Published online December 14, 2015 www.pnas.org/cgi/doi/10.1073/pnas.1507459112 Downloaded by guest on October 4, 2021 consequences of constitutive activation of CARD11 signaling in lation (Fig. S1B). These results are in accordance with published PNAS PLUS normal B cells remain unclear, and the downstream effectors that data (14) and demonstrate that forced expression of CARD11 mediate the aberrant CARD11 activity remain to be identified. (L225LI) is sufficient to induce constitutive NF-κB signaling Here, we generated a mouse model for conditional expression and to trigger B-cell activation. Because the CARD11(L225LI) of a human DLBCL-derived CARD11(L225LI) gain-of-function mutant induces stronger NF-κB activation than other patient- mutant and demonstrated that CARD11(L225LI) autonomously derived or artificially generated CARD11 gain-of-function associates with BCL10 and MALT1 and cooperatively activates variants (13, 14), we used CARD11(L225LI) to study enforced NF-κB and JNK signaling, resulting in a rapidly lethal lympho- CARD11 signaling in vivo. To this end, we introduced a human proliferative disorder. Moreover, we observed constitutive JNK Card11(L225LI) cDNA fused to a hemagglutinin (HA) tag pre- activation in primary human ABC-DLBCL specimens and showed ceded by a loxP-flanked (FL) transcriptional and translational that JNK inhibition was toxic to murine CARD11(L225LI)- STOP cassette into the mouse genome at the ubiquitously expressing B cells and human ABC-DLBCL lymphoma cells. expressed ROSA26 locus (Fig. S2) (15). Crossing CARD11 FL Our data demonstrate that the forced activation of CBM sig- (L225LI)stop mice with CD19-Cre transgenic animals (16) naling is sufficient to drive lethal lymphoproliferation in vivo and resulted in excision of the loxP-flanked STOP cassette specifically highlight JNK as a potential target for the treatment of ABC- in the B-cell lineage as early as the pre–B-cell stage. Subsequent DLBCL patients. bicistronic expression of CARD11(L225LI), together with en- hanced green fluorescent protein (eGFP), allowed fluorescence Results monitoring of the CARD11(L225LI)-expressing cells. For sim- FL CARD11(L225LI) Expression in B Cells Drives a Rapidly Lethal Lympho- plicity, we refer to the CD19-Cre and CARD11(L225LI)stop proliferative Disease. To investigate constitutive active CARD11 double transgenic mice throughout this study as CARD11 signaling, we first introduced the human lymphoma-derived (L225LI)CD19-Cre mice. CARD11(L225LI) mutant into the mature B-cell lymphoma line Strikingly,
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