Biology subjects

D'Avola, A.

Publications and source records attributed to D'Avola, A..

3 recordsLinked to original sources

bioRxiv2021

PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma

The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B-cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate limiting enzyme in this pathway, leads to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis is a characteristic of germinal center B-cell derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induces apoptosis in lymphoma cells reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.

immunology↗

bioRxiv2020

KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

Loss-of-function mutations in KMT2D are a striking feature of the germinal centre (GC) lymphomas, resulting in decreased H3K4 methylation and altered gene expression. We hypothesised that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would re-establish H3K4 methylation and restore the expression of genes repressed upon loss of KMT2D. KDM5-inhibition increased H3K4me3 levels and caused an anti-proliferative response in vitro, which was markedly greater in both endogenous and CRISPR-edited KMT2D mutant DLBCL cell lines, whilst tumour growth was inhibited in KMT2D mutant xenografts in vivo. KDM5-inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell receptor signalling and altered expression of BCL2 family members, including BCL2 itself, allowing it to synergise with agents targeting these pathways. KDM5-inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC-lymphomas.Statement of significance We detail a novel way of reverting the effects of loss-of-function mutations in the histone methyltransferase KMT2D by inhibiting the KDM5 demethylase family, increasing levels of H3K4me3 and restoring expression of KMT2D regulated genes.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2019

Kinobead profiling reveals reprogramming of B-cell receptor signaling in response to therapy within primary CLL cells.

Signaling via the B-cell receptor (BCR) is critical for driving CLL pathobiology, promoting both malignant cell survival and disease progression. However, understanding of this pathway is limited, particularly in relation to potential changes in response to therapy. Here, we describe a kinobead-based protocol, used in conjunction with mass-spectrometry to study surface-IgM signaling in primary CLL cells. We identified a fingerprint of over 30 kinases which displayed unique, patientspecific response following sIgM stimulation. Matched analysis of CLL cells in samples taken from clinical trials showed that BCR-induced kinome responses altered between baseline and disease progression in patients who relapsed from chemoimmunotherapy. Moreover, adaptive changes to BCR signaling were also observed in CLL cells from clinical trial patients receiving ibrutinib; longitudinal profiling revealed increased signaling despite BTK inhibition. Collectively, these data comprise the first comprehensive investigation into BCR signaling response within CLL where kinobead profiling reveals unique evidence of adaptive reprogramming in response to therapy.

cancer biology↗