Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two most common forms of mature B-cell lymphoma, together accounting for over 70% of all diagnoses. Both diseases remain a significant clinical challenge, as a significant patient population does not achieve durable remissions following conventional therapeutic strategies. The identification of molecular mechanisms that are responsible for tumor initiation and maintenance, and could be vulnerable to targeted therapeutic intervention, represents a research imperative in order to advance our ability to cure these diseases. Somatic mutations leading to inactivation of the KMT2D methyltransferase emerged as the most common genetic lesion in FL (80% of cases) and DLBCL (~30% of cases), suggesting a prominent role for epigenetic perturbations in the pathogenesis of these cancers (Pasqualucci et al., Nature Genetics 2011; Morin et al., Nature 2011). Indeed, conditional inactivation of KMT2D in vivo leads to the expansion of germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and cooperates with BCL2 deregulation to increase the incidence of tumors recapitulating phenotypic and genetic features of the human FL/DLBCL, thereby establishing KMT2D as a bona fide tumor suppressor gene (Zhang et al., Nature Medicine 2015; Ortega- Molina et al., Nature Medicine 2015). However, GC-specific deletion of KMT2D individually was insufficient to drive tumor formation, suggesting the requirement of additional cooperating events. We observed that KMT2D mutations are frequently associated with alterations in the CREBBP/EP300 acetyltransferases, found in 60% of KMT2D-mutated FL and ~25% of KMT2D-mutated de novo DLBCL. Both alterations represent early lesions in lymphomagensis (Pasqualucci et al, Cell Reports 2014). Moreover, CREBBP acetylates the KMT2D protein in vivo; finally, the chromatin-binding pattern of these two proteins significantly overlaps at GC-specific super- enhancers (Zhang et al., Nature Medicine 2015 and Cancer Discovery 2017). These data suggest that KMT2D and CREBBP cooperate in B cell lymphomagenesis by coordinately regulating common and specific programs. Building on these results, the general goal of this project will be to elucidate the cooperative role of KMT2D and CREBBP in normal and transformed GC B cells, with three Specific Aims: i) identify the transcriptional program coordinately or combinatorially regulated by these two proteins in normal GC B cells, and disrupted in B cell lymphomas with concurrent inactivating mutations, and the role of CREBBP-mediated acetylation on KMT2D function; ii) investigate the role of KMT2D/CREBBP enhancer binding in favoring chromosomal translocations and aberrant somatic hypermutation; and iii) examine the synergistic role of combined KMT2D/CREBBP deficiency in lymphoma initiation in vivo. We anticipate that the results obtained from these studies will impact our current understanding of the pathogenesis of these diseases, by providing new insights on the mechanisms initiating neoplastic transformation and on their specific therapeutic targeting. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
RESEARCH NARRATIVE Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the two most common forms of B cell lymphoma, remain incurable in a significant proportion of patients. This research proposal seeks to identify the B cell specific molecular circuitry that is coordinately regulated by KMT2D and CREBBP (the two most commonly mutated genes in these cancers), and to uncover mechanisms and vulnerabilities that are specific to the mutant cells. The outcome of these studies is expected to further our understanding of the pathogenesis of these common cancers, and to provide new insights for the development of better diagnostic and therapeutic tools.
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