BCRlossToBWinner · Genetic determinants promoting resistance to BCR-loss in B-cell lymphomas
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-12-01 → 2023-11-25
- EU contribution
- €183,473
- Participants
- 2
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Genetic determinants promoting resistance to BCR-loss in B-cell lymphomas
BCRlossToBWinner aims at disclosing novel molecular, genetic and biomechanical mechanisms promoting the survival of B cells in supra-physiologic conditions (i.e. loss of BCR expression), leading to abnormal B cell expansion and B cell transformation. Specifically, we studied the contribution of FOXO1 mutations to promote cellular fitness in BCR-deficient Myc-transformed lymphoma B cells (Aim #1), and we screened for molecular determinants supporting the growth of BCR-negative lymphoma B cells ( Aim #2). Using genetic, molecular and cellular biology approaches to establish mouse-derived MYC-driven lymphoma cellular models carrying FOXO1 mutations frequently observed in human B-cell malignancies, we unveiled an unrecognized function for mutant FOXO1 proteins in constitutively activating signaling pathways controlled by the B cell receptor (BCR) to sustain lymphoma growth and respond to nutrient starvation conditions, thus providing fitness advantage to MYC-driven lymphoma B cells. Indeed, experimental observations (cellular behavior, signaling features, cellular fitness in response to BCR-deletion) confirmed the relevance of the generated cellular models as an invaluable tool to effectively address a number of yet unsolved questions, in part represented by unanticipated hypothesis inspired by this project, opening novel perspectives in the field of B-cell lymphomagenesis. Moreover, through a large-scale pharmacological screening we identified compounds interfering with the growth of MYC-driven B cell lymphomas, disclosing potentially unexplored synthetically lethal interactions between the loss of BCR-expression and specific cellular pathways. During this action, we finally identified a crosstalk between BCR signaling and the regulation of immune-modulatory molecules, thus intertwining the expression of a functional Ig-receptor with effective immune-evasion, possibly expanding the therapeutic landscape for the treatment of aggressive lymphomas according to their BCR-status and (FOXO1) mutational profile. Accordingly, experimental data and observations derived from the Action provide a solid conceptual infrastructure supporting the development of novel hypothesis proposing the involvement of FOXO1 mutations to predispose normal B cells to malignant transformation, as well as their cooperation with defined oncogenic events shaping evolutionary trajectories underlying the transformation of B cell lymphomas into aggressive and still uncurable B cell malignancies (i.e. high-grade B cell lymphomas).
Data: CORDIS, © European Union
Project objective
Loss of B-Cell Receptor (BCR) in lymphoma B cells leads to attenuated PI3K/AKT signaling and altered Myc-dependent transcriptional output, resulting in a competitive disadvantage in BCR-deficient lymphoma cells. The acquisition of genetic events restoring signaling competence is sufficient to improve cellular fitness in BCR-deficient lymphomas. A fraction of Non-Hodgkin-B-cell lymphomas carry missense mutations in FOXO1, a transcription factor essential during B cell development, and a main target of the PI3K/AKT pathway, which relays survival signals downstream of the BCR. In preliminary studies, we found that cells with FOXO1 mutations rewire their signaling status showing a) activation of stress-activated protein kinases (SAPKs) and PI3K/AKT, b) altered responses to key upstream receptors, such as CD40 and BCR, and c) improved fitness. In this context, I propose to investigate whether FOXO1 mutations are able to provide resistance to BCR-loss in transformed B cells, by favoring the activation of PI3K/AKT, SAPK/JNK (and potentially other) signaling pathways. This hypothesis will be tested using mouse and human models that allow conditional deletion of the BCR in FOXO1 mutant B cells, determining whether expression of FOXO1 mutations is: a) sufficient to release normal B cells from BCR-dependency, and b) able to restore competitive fitness to BCR-deficient lymphomas. Moreover, combining CRISPR/Cas9 and chemical screenings, I propose to identify novel factors sustaining the growth of lymphoma cells that lost BCR expression. Overall, this research proposal will address relevant, yet unanswered questions in the biology of B cell lymphomas, providing a better understanding into the complexity of signaling competence in normal and transformed B cells, and identifying novel factors promoting independence from BCR signaling, to be exploited as therapeutic targets for the treatment of B cell lymphomas resistant to BCR-specific inhibitors.
Original text from CORDIS.
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Data: CORDIS, © European Union