ZAP70-related severe combined immunodeficiency (SCID) is a defect of the immune system characterized by absent or extremely low CD8+ T-cells and abnormal T-cell receptor signaling. This form of SCID is relatively rare with about 20 cases currently described in the literature and typically presents in infancy with recurrent opportunistic infections, failure to thrive, and gastrointestinal sympto...

The non-receptor tyrosine kinase Syk (spleen tyrosine kinase) is a pharmaceutical relevant target because its over-activation is observed in several autoimmune diseases, allergy, and asthma. Here we report the identification of two novel inhibitors of Syk by high-throughput docking into a rare C-helix-out conformation published recently. Interestingly, both compounds are slightly more active on...

BACKGROUND To understand complex biological signalling mechanisms, mathematical modelling of signal transduction pathways has been applied successfully in last few years. However, precise quantitative measurements of signal transduction events such as activation-dependent phosphorylation of proteins, remains one bottleneck to this success. METHODOLOGY/PRINCIPAL FINDINGS We use multi-colour im...

Two recent studies reported whole-genome sequencing of chronic lymphocytic leukemia (CLL) samples and found repeated mutations in the XPO1 and NOTCH1 genes. XPO1 was found mutated in 2.4% of cases, while NOTCH1 was found mutated in 12.2% or 15.1% of CLL samples. Here we report the results of sequencing of XPO1 and NOTCH1 in 186 CLL cases. Our results confirmed frequency of XPO1 mutations. Howev...

BACKGROUND Increased CD38 expression by leukemic cells has been suggested as an adverse prognostic factor in B-CLL. Several approaches have been proposed to quantify its level of expression by flow cytometry. METHODS We compared the use of (i) the percentage of CD38 positive cells, (ii) CD38 antibodies bound per cell (ABC), and (iii) a semi-quantitative method based on the shape of the CD38 h...

ZAP-70 in chronic lymphocytic leukemia (CLL) has been associated with enhanced Bcell receptor (BCR) signaling, survival and migration. We investigated whether ZAP-70 can directly govern migration and the underlying mechanisms. In the ZAP-70 stablytransfected Ramos cell line, IgM stimulation but no IgD enhanced phosphorylation of ERK1/2, Akt and Syk, and delayed IgM and CD79b internalization. In...

Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) show varying responses to conventional therapy, and this might be contributed to the differentiation stage of the tumor B-cells. The aim of the current study was to evaluate a panel of kinases (ZAP70, PKC-b I and II and phosphorylated PKB/Akt) and phosphatases (PTEN, SHP1 and SHP2) known to be frequently deregulated in lymphoid malig...

Activated chemokine receptor initiates inside-out signaling to transiently trigger activation of integrins, a process involving multiple components that have not been fully characterized. Here we report that GM-CSF/IL-3/IL-5 receptor common beta-chain-associated protein (CBAP) is required to optimize this inside-out signaling and activation of integrins. First, knockdown of CBAP expression in h...