Genetic determinants promoting resistance to BCR-loss in B-cell lymphomas

Descripción del proyecto

Factores genéticos de la resistencia en linfomas de células B con receptores de células B negativos

La señalización de los receptores de las células B (BCR, por sus siglas en inglés) resulta crucial para el desarrollo normal de las células B y favorece la supervivencia y el desarrollo de las células B malignas en pacientes con leucemias o linfomas de células B. La pérdida de BCR en las células B de los linfomas da lugar a una atenuación de la señalización PI3K/ATK y a una regulación transcripcional dependiente de Myc alterada, lo que da origen a una desventaja competitiva en las células del linfoma deficientes en BCR. El proyecto BCRlossToBWinner, financiado con fondos europeos, propone investigar si las mutaciones FOXO1 son capaces de proporcionar resistencia a la pérdida de BCR en células B transformadas al favorecer la activación de PI3K/AKT, SAPK/JNK u otras vías de señalización. La investigación ayudará a identificar nuevos factores que fomenten la independencia de la señalización de los BCR como objetivos terapéuticos para el tratamiento de los linfomas de células B resistentes a los inhibidores específicos de los BCR.

Objetivo

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.