Dear All,

On Thursday (26.06) we will Prof. Gianluca Baldanzi from the University of Eastern Piedmont "Amedeo Avogardo" in Novara, Italy. His lecture will be entitled: "Diacylglycerol kinases in primary immunodeficiencies and Acute Myeloid Leukemia". The lecture will take place at 3 p.m. in the CN lecture hall and it will be followed by a get together.

Abstract

The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, impaired humoral and cellular immunity, and thrombocytopenia. There are multiple hematopoietic cell defects in WAS, such as impaired T-cell functions, markedly reduced platelet number and size, and decreased migration and response to agonists in several cell lineages. By studying diacylglycerol signaling in X-linked lymphoproliferative disease, we discovered that diacylglycerol kinase alpha (DGKα) acts as a negative regulator of T-cell activation and its activity is limited by the direct binding to the Wiskott-Aldrich syndrome protein (WASp) downstream to the SAP adaptor (mutated in another genetic disease: Duncan’s disease). We are currently investigating the role of WASp and DGKα at the immune-synapse to improve our understanding of the role played by this signaling pathway in T-cell signaling and activation.

In addition, the role of DAG in promoting megakaryopoiesis and platelet aggregation suggests that DGKα may also be a key regulator of platelet formation and function. Indeed, DGKα inhibition could accelerate megakaryopoiesis in vitro and in vivo, enhancing cell elongation and spreading and boosting surface differentiation marker induction (CD41). We speculate that DGKα hyperactivity, due to a lack of WASp, decreases DAG, contributing to the altered thrombopoiesis and defective platelet function observed in WAS patients. Indeed, DGKα inhibition rescues some of the defects of WASp-deficient cell models. Our data support the potential of DGKα as a druggable therapeutic target whose inhibition could be beneficial for WAS patients, promoting platelet formation and function.

Finally, we investigated Acute Myeloid Leukemia (AML). Several DGK isoforms are highly expressed in AML, and both hematopoiesis and AML development are in part controlled by either DGKα or DGKζ , which are proposed as targets for a novel therapeutic approach. In cellular models, we pharmacologically inhibited or silenced either DGKα or DGKζ and evaluated their role by measuring cell viability and apoptosis/necrosis rate in a panel of AML cell lines. Each AML cell line resulted differently impacted by DGKα and DGKζ pharmacological inhibition or silencing. These data indicate that DGKs are putative therapeutic targets for AML patients, playing a relevant and isoform-specific role. Moreover, we observed that the expression level of each isoform is not a predictor of responsiveness to isoform-specific inhibitors.

The lecture will take place at 3 p.m. in the CN lecture hall and it will be followed by a get together.

Hope to see you all there,

Tomasz Wypych