Role of replication stress during MYC-dependent B cell lymphomagenesis

Deregulated expression of the MYC proto-oncogene is a frequent feature of a significant fraction of human cancers. Despite the extensive knowledge on its biology accumulated over the years, the precise molecular mechanisms that sustain its oncogenic activity still remain unclear. Deregulation of MYC expression in mouse B cells and several other cell types causes DNA replication stress and subsequent DNA damage, a phenomenon that we described to depend on the ability of this proto-oncogene to control DNA replication initiation. Replication stress is often seen in early stage cancers of different tissue origin, and is believed to be a consequence of oncogene activation. However, we do not know whether this phenomenon actively contributes, and how, to cancer initiation and/or progression. The goal of this project is to answer these questions using a model of MYC-dependent B cell lymphomagenesis. We are devising ways to manipulate MYC’s ability to trigger replication stress, or modify the ‘quality’ of the replication stress response to MYC deregulation. We hypothesize that pathways coping with replication stress define how MYC drives cellular transformation and cancer and hence, manipulation of these pathways -or their differential activity in different cellular contexts- will determine MYC’s oncogenic activity.

This work has been supported by a ‘Howard Temin’ K99/R00 Career Development Award by the National Institutes of Health/ National Cancer Institute (R00-CA151827) to David and an NCI T32 award to Jongkuen.

A rough scheme illustrating the idea behind the project: how deregulation of DNA replication initiation by MYC acts as a source of DNA damage and genomic instability in cancer cells.

Oncogenes as source of mutational noise and clonal diversity during cancer initiation

The heterogeneous repertoire of mutations in each cancer results in complex cellular architectures, built by multiple genetically distinct subclones that largely define the biology and clinical features of the disease. Such heterogeneity endows tumors with the ability to progress, resist targeted therapies, and relapse. These distinct genotypic features could conversely be used to trace the disease in individuals at risk and for its early detection, when treatment would be most effective.

However, despite the vast information on cancer mutational repertoires, the principles that govern the acquisition of selected mutations during cancer initiation remain unknown. We hypothesize that specific factors limit the choice of newly acquired genetic mutations during cancer initiation to shape the genetic landscape of cancers.

It is believed that the bulk of mutations in cancer cells are acquired during the early (premalignant) stages of the disease, but the drivers of mutational accrual in most cancers types are unknown. In fact, only a handful of cancers show early mutations in genes involved in the maintenance of genomic stability. This project explores whether oncogenes, through the generation of DNA damage and “mutational noise”, can drive genetic heterogeneity and affect clonal evolution in cancer. To address this question, we use a combination of conditional mouse targeting with ad hoc engineered oncogenes and multicolor lineage tracing strategies. Additionally, we will determine the influence of the cellular context on shaping the repertoire of secondary genetic lesions, by analyzing the genetic landscape of premalignant disease in mouse cohorts with selective activation of MYC in specific B cell subsets. Clear knowledge on how cancer cells alter and “select” their genomic repertoire could help us devise strategies aimed at blunting cancer’s ability to evolve and effectively adapt to medical interventions.

This work has been supported by the Leukemia Research Foundation and the Louis Sklarow Memorial Trust, and a National Cancer Center postdoctoral fellowship to Gabriele.