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B-cell receptor driven MALT1 activity regulates MYC signaling in mantle cell lymphoma

ABSTRACT: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by poor clinical outcome. Recent studies revealed the importance of BCR signaling in maintaining MCL survival. However, it remains unclear which role MALT1, an essential component of the CARD11-BCL10-MALT1 (CBM) complex that transfers BCR signaling to the NF-kB pathway, plays in the biology of MCL. Here we show that a subset of MCLs is addicted to MALT1, as its inhibition by either RNA or pharmacologic interference induced cytotoxicity both in vitro and in vivo. Gene expression profiling following MALT1 inhibition demonstrated that MALT1 controls a MYC-driven gene expression network predominantly through increased MYC protein stability. Thus our analyses identify a previously unappreciated regulatory mechanism of MYC expression. Investigating primary mouse splenocytes, we could demonstrate that MALT1 induced MYC regulation is not restricted to MCL, but represents a common mechanism of MYC regulation. MYC itself is pivotal for MCL survival as its downregulation and pharmacologic inhibition induced cytotoxicity in all MCL models. Collectively, these results provide a strong mechanistic rationale to investigate the therapeutic efficacy in targeting the MALT1-MYC axis in MCL patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81552 | GEO | 2017/02/24

SECONDARY ACCESSION(S): PRJNA321973

REPOSITORIES: GEO

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Project description:Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a para-caspase required for B-cell receptor (BCR)-mediated NF-κB activation. We sought to examine the role of MALT1 in B-ALL and determine the biological consequences of inhibiting its activity. First, we tested MALT1 expression by immunoblot in B-cell acute lymphoblastic leukemia (B-ALL) using 16 cell lines representing the disease spectrum and found that MALT1 was expressed in all cell lines at different levels. To determine sensitivity to MALT1 inhibition we used two molecules: Z-VRPR-fmk, a highly selective MALT1 blocking peptide, and MI2, a small molecule MALT1 inhibitor. Z-VRPR-fmk resulted in a dramatic cell growth inhibition in most of our B-ALL cell lines, with appropriate positive (JEKO) and negative (JURKAT) controls. We did not observe a clear correlation between MALT1 level and degree of sensitivity to Z-VRPR-fmk. Interestingly, the two ibrutinib-resistant cell lines RS4;11 and 697, were amongst the top sensitive cell lines to MALT1 inhibition. A similar pattern of cell sensitivity was observed when these cell lines were treated with MI2, with a positive correlation between the IC50 of MI2 and the amount of cell growth inhibition with Z-VRPR-fmk (r=0.74 95%CI (0.47-0.88) p=0.0001). Interestingly, freshly collected PBMCs from patients with B-ALL showed a high sensitivity to MI2 following incubation at serial dilutions for 48h. Furthermore, apoptotic and cell cycle analyses showed a dose-dependent apoptotic induction and cell cycle arrest in the studied ell lines. Surprisingly, the proteolytic activity of MALT1, studied by measuring its ability to cleave its targets such as CYLD, BCL10, and RelB, was not detected at baseline, nor after proteasomal inhibition with MG-132 or following crosslinking of pre-BCR with anti-IgM in pre-B ALL, the latter successfully increased AKT phosphorylation. Collectively, these data are suggestive of distinct role for MALT1 in B-ALL. To explore this possibility, we used RNA sequencing to determine the changes in gene expression profiling following an 8h MI2 treatment in 12 sensitive B-ALL cell lines. Out of 39,514 tested genes, there were 160 genes whose expression changed ≥ 2-fold at P < 0.05 (84 down- and 76 up-regulated). Gene Set Enrichment Analysis (GSEA) identified 34 Hallmark and Oncogenic Signature gene sets relevant to B-ALL that were all downregulated by MI2 (FDR < 10%, and normalized enrichment score (NES) ≥ 1.50). Among those gene sets the c-MYC, gene signatures stood out as the most affected, further confirmed with downregulation of the MYC protein by immunoblot analysis in MI2-sensitive cell lines. In conclusion, MALT1 plays a critical role in B-ALL survival likely through a novel mechanism that involves MYC regulation, independently from pre-BCR/BCR signaling.

Project description:MALT lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the NF-ÎºB pathway. Gastric MALT lymphomas harboring such translocation do not respond to H. pylori eradication, while those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 24 MALT lymphomas (15 translocation-positive, 9 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-ÎºB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions showed that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-ÎºB target genes, particularly TLR6, CCR2, CD69 and BCL2, while translocation-negative cases were featured by active inflammatory and immune responses, such as IL8, CD86, CD28 and ICOS. Separate analyses of the genes differentially expressed between translocation-positive and negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10 mediated NF-ÎºB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors. This study compares MALT with other lymphomas, namely follicular lymphomas (FL) and mantle cell lymphomas (MCL), and investigates the molecular mechanisms of the lymphomagenesis between translocation-positive versus -negative MALT lymphoma cases in order to derive the pathways leading to MALT lymphoma pathogenesis. The study uses fresh frozen tissues from 24 MALT lymphoma cases with 7 FL and 7 MCL. Samples were run on the HG-U133A, HG-U133B, and HG-U133 plus2 GeneChips.

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B-cell receptor driven MALT1 activity regulates MYC signaling in mantle cell lymphoma

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