Malt1 Signaling Pathway as a Drug Target

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Abstract: The development of lymphomas and leukemias is frequently caused by chromosomal translocations that deregulate cellular pathways of differentiation ...
Current Drug Targets, 2006, 7, 000-000

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The Bcl10 / Malt1 Signaling Pathway as a Drug Target in Lymphoma P. Jost, C. Peschel and J. Ruland* Third Medical Department, Technical University of Munich, Klinikum rechts der Isar, Ismaninger Str. 22, 81675 Munich, Germany Abstract: The development of lymphomas and leukemias is frequently caused by chromosomal translocations that deregulate cellular pathways of differentiation, proliferation or survival. The molecules that are involved in these aberrations provide rational targets for selective drug therapies. Recently, several disease specific translocations have been identified in human MALT lymphoma. These aberrations either upregulate the expression of BCL10 or MALT1 or induce the formation of API2-MALT1 fusion proteins. Genetic and biochemical experiments identified BCL10 and MALT1 as central components of an oligomerization – ubiquitinylation – phosphorylation cascade that activates the transcription factor NF-B in response to antigen receptor ligation. Deregulation of the signaling cascade is directly associated with antigen independent MALT lymphoma growth. Here we provide an overview of the physiological and pathological functions of BCL10 / MALT1 signal transduction and discuss the potential of this pathway as a drug target.

Key Words: Lymphoma, Malt1, Bcl10, API2-MALT1, NF-B, antigen receptor, chromosomal translocation, fusion protein. INTRODUCTION Hematological malignancies are typically characterized by recurrent and disease specific chromosomal translocations that are directly responsibly for cell transformation, tumor cell maintenance and disease progression [1,2]. Generally, these translocations disrupt normal cellular functions of central signaling molecules through either transcriptional upregulation or by generating gene fusions that encode for novel chimeric proteins. Typical examples for the deregulated expression of proto-oncogens include cyclin D1/BCL1 in mantle cell lymphoma through the translocation t(11;14)(q13;32), overexpression of BCL2 in follicular lymphoma by t(14;18)(q32;q21), and activation of c-MYC by t(8;14)(q24;q32) in Burkitt lymphoma [3]. A prototypic oncogenic fusion protein is BCR/ABL that results from the Philadelphia translocation t(9;22) (q34;q11) in chronic myeloid leukemia (CML) and Philadelphia positive acute lymphoblastic leukemia [4]. The functional studies of translocation products in hematological malignancies uncovered many basic principles of tumor cell biology. Often, the oncogenes that are characteristically translocated in distinct malignancies were later found to be essential for common cellular pathways that are deregulated in a broader spectrum of diseases. The chromosomal translocations in leukemias and lymphomas repeatedly defined critical regulators of cell proliferation, differentiation or survival and provide drug targets for selective therapies. This is impressively exemplified by the identification of BCR/ABL as an oncogenic tyrosine kinase that controls cell proliferation [5]. Consistent with its causal role in tumorigenesis the inhibition of BCR/ABL kinase activity with the targeted drug imatinib has been proven effective in treating t(9;22) positive CML or ALL [6]. CHROMOSOMAL TRANSLOCATIONS IN MALT LYMPHOMA DEREGULATE BCL10 OR MALT1 Recently, several novel chromosomal translocations have been characterized in B cell lymphomas of the mucosa associated lymphatic tissue (MALT) type [7]. MALT lymphoma is the most common type of extra-nodal non-Hodgkin´s lymphoma (NHL) and typically develops in the stomach, lungs, salivary or thyroid glands. The disease is usually connected to chronic infections or autoimmunity and the majority of MALT lymphoma cases are Helicobacter pylori-associated gastric MALT B cell tumors [8]. As an *Address correspondence to this author at Third Medical Department, Technical University of Munich, Klinikum rechts der Isar, Ismaninger Str. 22, 81675 Munich, Germany; Tel: +49 - 89 - 4140 6104; Fax: +49 - 89 4140 4865; E-mail: [email protected] 1389-4501/06 $50.00+.00

antigen, H. pylori initially drives the formation of acquired MALT within the gastric mucosa. At early lymphoma stages the malignant B cell proliferation is dependent on the presence of the antigen and antibiotic eradication can result in complete tumor remission [9,10]. However, at more advanced stages tumor B cell expansion becomes antigen-independent and chemo- or radiotherapeutic interventions are required. Clinical studies found that the chromosomal translocation t(11;18)(q21;q21) and t(1;14)(q22;q32) directly correlate with nonresponsiveness to antibiotic eradication therapy and / or advanced disease [11,12,13]. Cloning of the chromosomal breakpoints identified two novel oncogenes: MALT1 on chromosome 18q21 and BCL10 on chromosome 1q22 [14,15,16,17,18,19]. The translocation t(11;18)(q21;q21) fuses the MALT1 gene to the API2 (Apoptosis inhibitor 2) locus on chromosome 11 and generates an API2MALT1 fusion protein. The translocation t(1;14)(q22;q32) brings the BCL10 gene under the control of the enhancer region of the immunoglobulin (Ig) heavy chain gene locus on chromosome 14 and deregulates its expression. Additional translocations involving MALT1 or BCL10 have also been identified in MALT1 lymphoma. Translocation t(14;18)(q32;q21) brings the full-length wildtype MALT1 gene under the control of the Ig heavy chain locus [20, 21], and t(1;2)(p22;p12) translocates BCL10 to the Ig kappa light chain locus [22]. STRUCTURAL ORGANIZATIONS OF MALT1, API2MALT1 AND BCL10 PROTEINS The wild type MALT1 protein resembles a so-called mammalian paracaspase that is related to meta-caspases of protozoa, fungi or plants [23]. Structurally, the protein is characterized by an amino-terminal death domain followed by two immunoglobulin (Ig) like domains and a carboxy-terminal region that resembles the catalytically active site of caspase proteases followed by an additional Ig-like domain [24] (Fig. 1A). However, no proteolytic activity has been detected for MALT1 so far [25]. The API2 protein contains three baculovirus IAP repeats (BIR), a central CARD domain and a C-terminal RING finger domain (Fig. 1A). API2 can block the activity of caspases 3, 7 and 9 [26]. The translocation t(11;18)(q21;q21) breakpoints within the API2 gene occur all distal of the BIR domain encoding exons and proximal of the RING finger domain. In the MALT1 gene, the breakpoints are either up- or downstream of the exons that encode the Ig repeats but always proximal of the caspase-like domain [27]. Since the API2-MALT1 fusion transcripts are always in frame, the resulting fusion proteins constantly contain three intact API2 BIR domains and the full MALT1 caspase-like domain either with or © 2006 Bentham Science Publishers Ltd.

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without Ig repeats (Fig. 1B). The selection for the BIR domains and the caspase-like region in the fusions suggest a functional synergy in tumor development. The BCL10 protein is a 32 kDa molecule that contains an amino-terminal caspase recruitment domain (CARD) and a Ser/Thrrich carboxyl terminus (Fig. 1A). Initially the protein was also called CIPER, CARMEN, CLAP or because it shares strong homology with the viral protein E10 of the equine herpes virus 2 it was named mE10 or c-E10 [28-31]. The CARD region of BCL10 mediates homophilic CARD-CARD interactions and can induce auto-oligomerization of BCL10 molecules [30-32]. In addition, it is able to bind to CARD motifs of other proteins including CARMA1 (also known as CARD11 or BIMP2) [33-35]. BCL10 AND MALT1 COOPERATE IN NF-B ACTIVATION Although the BCL10 and MALT1 genes are involved in mutually exclusive translocations in human MALT lymphoma the corresponding proteins are able to directly bind to each other and to cooperate in cell signaling. Their physical interaction is mediated by the Ig-like domains of MALT1 and a short stretch of amino acids that follow the BCL10 CARD domain [36]. Overexpression of BCL10 in cell lines activates NF-B and this signal can be strongly enhanced by co-overexpression of MALT1. In contrast, overexpression of wildtype MALT1 on its own does not induce NF-B activation [36,23]. NF-B represents a small family of dimeric transcription factors that serve as master regulators of proliferation, survival and effector function in immune cells [37]. In resting cells, NF-B dimers are retained in an inactive state within the cytoplasm by binding to inhibitory B (IB) proteins. A variety of cell activating

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stimuli can activate NF-B by inducing site-specific phosphorylation of IB proteins at two conserved serine residues. The phosphorylation of IBs is catalyzed by an inducible multi-protein kinase called inhibitory B kinase (IKK) [38], which is able to integrate signals from multiple upstream pathways. This kinase complex is composed of two catalytic subunits, IKK and IKK, and the regulatory subunit IKK / NEMO. Signal induced phosphorylation of IB proteins marks these molecules for ubiquitinylation and subsequent proteolysis within the 26S proteasome. This event frees NF-B proteins in the cytoplasm and allows their translocation into the nucleus to activate gene transcription. NF-B target genes include positive cell cycle regulators like cyclin D1, cyclin D2, c-myc and c-myb [39, 40, 41, 42], as well as potent anti-apoptotic factors like caspase inhibitors of the IAP family, the BCL2 family members A1 and BCL-XL and c-FLIP (cellular FLICE inhibitor protein) [43]. Whereas controlled activation of NF-B is required for normal immune cell division, activation and survival during adaptive or innate responses, uncontrolled NF-B activity can result in continuous cell proliferation and blockage of apoptosis. Consistently, aberrant NF-B signaling has been linked to the development of a variety of leukemias and lymphomas and other human cancers [43]. The specific functions of BCL10 and MALT1 in NF-B regulation were uncovered in gene targeted mice with disruptions of either the Bcl10 or Malt1 loci [44, 45, 46, 47]. Both molecules were found to be essential for normal lymphocyte differentiation as the disruption of either gene affects early thymocyte maturation and impairs the development of B1 B cells, follicular B cells or marginal zone B cells, the normal counterparts of MALT lymphoma B cells. Bcl10 and Malt1 deficient mice exhibit severe combined immunodeficiency with dramatic impairments of humoral and cellular

Fig. (1). Schematic representation of BCL10, MALT1, API2 and API2-MALT1 fusion proteins type 1 and 2. (A) BCL10 is a 32-kD protein characterized by an amino-terminal CARD domain and a serine / threonine rich carboxyl terminus. The CARD domain of BCL10 can mediate auto-oligomerization but is also capable of interacting with CARD domains of other binding partners. MALT1 possesses an aminoterminal death domain, two immunoglobulin (Ig) like domains and a carboxy-terminal motif that resembles the catalytically active site of caspase proteases followed by an additional Ig repeat. The carboxy-terminal region is necessary for downstream ubiquitin ligase signaling. The API2 protein contains three baculovirus IAP repeats (BIR) in the amino-terminal region, a central CARD domain and a carboxy-terminal RING finger domain. (B) The IAP2-MALT1 translocations in MALT lymphoma always generate fusion transcripts that encode for chimeric proteins with three intact baculovirus IAP repeats important for auto-oligomerization and the full MALT1 caspase-like domain with the c-Terminal Ig repeat. Different types of fusion transcripts exist: type 1 fusions lack the two central Ig repeats of MALT1 and type 2 fusions contain these regions.

The Bcl10 / Malt1 Signaling Pathway as a Drug Target in Lymphoma

responses. Isolated lymphocytes from these animals are defective in cytokine production and show severely reduced proliferative responses upon stimulation of their T cell receptor (TCR) or B cell receptor (BCR). On the molecular level, Bcl10 and Malt1 are specifically required for the activation of NF-B in response to antigen receptor ligation. In contrast, neither of the two molecules are involved in antigen receptor induced calcium signaling or activation of mitogen activated protein kinases. Bcl10 and Malt1 are also dispensable for the activation of NF-B by proinflammatory cytokines like TNF- or IL-1. Together the studies of Bcl10 and Malt1 deficient mice uncovered that the Bcl10 / Malt1 complex serves as an essential regulator of lymphocyte proliferation via antigen receptor mediated NF-B activation.

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The recognition of antigen by the TCR or BCR activates a sequence of intracellular protein tyrosine phosphorylation events that are coordinated by Src, Syk and Tec kinases [48]. These events induce the re-organization of receptor proximal adapter proteins and the activation of downstream signaling enzymes including protein kinase C (PKC) isoforms. Finally, the receptor proximal signaling events result in the activation of IKK. The BCL10 / MALT1 complex connects PKC activation to the induction of IKK activity (Fig. 2). Lately much has been learned about the underlying molecular mechanism. In response to antigen receptor ligation and PKC activation, Bcl10 is recruited into the lipid raft fraction at the activated antigen receptor. This is accomplished by CARD-CARD mediated interaction with the scaffolding protein CARMA1 [49, 50]. This recruitment is believed to induce oligomerization of

Fig. (2). Physiological Function of the BCL10 / MALT1 signaling complex. Antigen receptor proximal signaling and PKC activation induce recruitment of BCL10 to the scaffold protein CARMA1 via CARD-CARD interaction, which results in BCL10 multimerization and oligomerization of its binding partner MALT1. Together with an ubiquitin-activating enzyme (E1), an ubiquitinconjugating complex (E2) that contains UBC13 and MMS2 and potentially together with TRAF6 the oligomerized MALT1 molecules mediate regulatory NEMO ubiquitinylation. Modified NEMO results in IKK activation and finally induces NF-B activity to mediate lymphocyte proliferation, survival and differentiation. Details see text. Abbreviations: PKC: protein kinase C; GUK: guanylate kinase; CC: coiled-coiled domain; SH3: Src-homology 3 domain; CARD: caspase recruitment domain; Ser/Thr: serine and threonine rich motif; Ig: immunoglobulin-like domain; DD: death domain; Casp-like: Caspase-like domain; IKK: inhibitory B kinase kinase; u: ubiquitinylation.

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BCL10 proteins, which subsequently results in the oligomerization of BCL10 bound MALT1 molecules. IKK complexes are corecruited to the lipid raft fraction and brought into close proximity to BCL10 and MALT1 [51]. Here, the oligomerized BCL10 / MALT1 complex controls IKK function by mediating regulatory ubiquitinylation of the NEMO subunit resulting in kinase activation [52, 53]. Whether ubiquitinylated NEMO induces a conformational change in IKK that results in self-activation or recruits an additional upstream activating kinase is still unclear. However, the BCL10 / MALT1 induced NEMO ubiquitinylation requires the presence of an intact MALT1 paracaspase domain, an ubiquitin activating en-

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zyme (E1) and an ubiquitin conjugating complex (E2) that contains UBC13 and MMS2 [52, 53]. It has been proposed that MALT1 directly possesses E3 ubiquitin ligase activity [52], or alternatively it has been suggested that oligomerized MALT1 indirectly controls NEMO ubiquitinylation by recruiting and activating the ubiquitin ligase TRAF6 [53]. FUNCTIONS OF BCL10 AND MALT1 IN MALIGNANCY The chromosomal translocations in MALT lymphoma uncouple the BCL10 / MALT1 complex from physiological upstream regulation and presumably all constitutively activate NF-B (Fig. 3). On

Fig. (3). Deregulation of BCL10 / MALT1 signal transduction by chromosomal translocations in MALT lymphoma. Several recurrent chromosomal translocations target BCL10 or MALT1 in human MALT lymphoma. The translocations t(1;14)(p22;q32), t(1;2)(p22;p12) and t(14;18)(q32;q21) deregulate the expression of the full-length BCL10 or MALT1 gene. The most common translocation t(11;18)(q21;q21) generates the novel chimeric fusion protein API2-MALT1. All translocation are uncoupling BCL10 / MALT1 function from physiological upstream regulation and induce constitutive downstream signaling to NF-B via ubiquitinylation of NEMO. Details see text. Abbreviations: CARD: caspase recruitment domain; Ser/Thr: serine and threonine rich motif; DD: death domain; Ig: immunoglobulin-like domain; Casp-like: Caspase-like domain; BIR: Baculovirus IAP repeat; IKK: inhibitory B kinase kinase; u: ubiquitinylation.

The Bcl10 / Malt1 Signaling Pathway as a Drug Target in Lymphoma

one hand, overexpression of BCL10 through Ig translocations might induce downstream signaling by constitutively oligomerize MALT1 molecules. On the other hand deregulation of full length MALT1 is likely to cooperate with endogenous BCL10 to consistently activate the NF-B pathway. The by far most common translocation, t(11;18)(q21;q21), however generates the API2-MALT1 fusion protein. Here, the region of wild type MALT1 that is responsible for the binding to BCL10 and required for signal induced oligomerization of MALT1 molecules is replaced by BIR domains of API2 [27] (Fig. 1B). The caspase-like domain that mediates downstream effector function of MALT1 stays intact in the fusion proteins. Since the BIR domains represent strong oligomerizing protein modules [54], the API2-MALT1 molecules constitutively autooligomerize in a BIR dependent manner without an exogenous stimulus [55,24]. The consequence is constitutive downstream signaling of the caspase-like domain and continuous ubiqitinylation of NEMO presumably resulting in activation of IKK [24]. The autonomous API2-MALT1 proteins are even able to signal in the absence of Bcl10 [45]. We therefore propose that all BCL10 and MALT1 translocations contribute to MALT lymphoma pathogenesis by activating NF-B independent of upstream antigen receptor signals. This would be a rational explanation for the antigen independent proliferation of tumor B cells that have acquired BCL10 or MALT1 translocation. This model would also be consistent with the finding that MALT lymphoma cases that do not respond to eradication therapy show strong nuclear accumulation of NF-B [56]. CONCLUSIONS AND PERSPECTIVES Cloning of the disease specific chromosomal translocation in human MALT lymphoma identified the oncogenes BCL10 and MALT1. Subsequently, a large series of complementary genetic and biochemical studies were able to demonstrate that the two proteins can directly bind to each other. They cooperate in the control of ubiquitin ligase activity to induce NF-B activation downstream of the antigen receptors. In line with these finding, the BCL10 / MALT1 deregulation in MALT lymphomas directly associates with antigen independent tumor cell growth. A therapeutic blockage of the pathway could therefore be a rational treatment option in these cases. Recently, the BCL10 and the MALT1 genes were also found to be deregulated in certain malignancies other than MALT lymphoma. The translocation t(14;18) involving MALT1 has been detected in mantle zone lymphoma (MZL), gene amplifications resulting in overexpression of the MALT1 protein were observed in Burkitt lymphoma as well as in MZL [21], and deregulation of BCL10 expression has been detected in mircoarray studies of pancreatic cancer [57]. These findings imply that a deregulation of BCL10 / MALT1 signaling could contribute to the development of other cancer types. This hypothesis clearly warrants further investigations but indicates that a selective blockage of BCL10 or MALT1 might potentially be beneficial in selected tumor subtypes beyond the MALT lymphoma. The complete inhibition of BCL10 / MALT1 signaling in an adult organism does not result in major abnormalities besides an immunodeficiency that is mainly based on an abolishment of T and B activation and effector function. This is evident in the Bcl10 and Malt1 deficient animals. Therefore, a blockage of this pathway in patients with lymphomatous disease would likely produce only manageable side effects. In addition, a pharmacological inhibition of BCL10 or MALT1 signaling could even be considered in certain non-malignant conditions with a T or B cell overreaction, such as autoimmunity or transplant rejections. ACKNOWLEDGEMENTS We thank Florian Bassermannn for critically reading the manuscript. J.R. is supported by a Max-Eder-Program-Grant from Deutsche Krebshilfe and by grants from Deutsche Forschungsgemeinschaft (SFB 455 and SFB 456).

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