Role of CREBBP missense mutations in lymphomagenesis

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RESEARCH SUMMARY Non-Hodgkin lymphomas are the 5th leading cause of cancer in the United States. Among them, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two most common forms, together accounting for over 60% of diagnoses. Despite remarkable advances in the treatment of these diseases, mortality remains high in as many as 40% of DLBCL patients, and FL, although regarded as an indolent disease, is incurable in advanced stages, often transforming into a highly aggressive malignancy. Relapse and transformation are linked to common mutated progenitor cells that maintain a subset of “founder” mutations present in the diagnostic dominant tumor clone. Therefore, improved understanding of the biology of the common precursor and the identification of mechanisms that could be vulnerable to targeted therapeutic intervention are therefore a priority in order to advance our ability to cure these diseases. Somatic mutations that inactivate the CREBBP acetyltransferase, including truncating and HAT domain missense mutations, emerged as the second most common genetic alteration in FL (70% of cases) and DLBCL (40% of cases belonging to the recently identified EZB/C3 genetic subset), revealing a prominent role for epigenetic aberrations in the pathogenesis of GC-derived lymphomas (Pasqualucci et al., Nature 2011; Morin et al., Nature 2011). CREBBP mutations represent early events during the tumor phylogenetic evolution, which are acquired by the common mutated precursor prior to the acquisition of additional oncogenic lesions (Pasqualucci et al, Cell Reports 2014; Okosun et al., Nature Genetics 2014). Indeed, reduced dosage of CREBBP synergizes with BCL2 deregulation to enhance the development of human-like FL/DLBCL. While truncating mutations have been extensively studied, the role of missense mutations remains largely unexplored. This is a significant gap when considering that missense mutations account for the overwhelming majority of CREBBP alterations in FL, and that different from truncating mutations, these alleles are expressed, suggesting that they could interfere with compensatory mechanisms by other acetyltransferases or the recruitment of transcription complexes. In line with this hypothesis, preliminary data from us and others have shown that the hotspot CREBBP missense HAT mutation induces distinct changes compared to those observed in CREBBP-deficient cells. Building on these results, the general goal of this project is to elucidate the impact of CREBBP missense (vs truncating) mutations on the malignant transformation of the precursor GC B cell in vivo, with three Specific Aims: i) investigate the in vivo role of the most common R1446H mutational hostspot in GC responses and lymphomagenesis; ii) identify the shared vs unique transcriptional programs dysregulated by missense vs truncating mutations in the GC B cell precursor; iii) investigate the role of CREBBP mutations in reprogramming the GC microenvironment. We anticipate that the results obtained from these studies will provide new insights on the mechanisms initiating neoplastic transformation and on their specific therapeutic targeting.