Wiskott-Aldrich Syndrome Protein in Lymphomagenesis: Unraveling the Interplay Between Somatic Mutations, B-cell Receptor Signaling and Actin Dynamics

Non-Hodgkin lymphomas (NHL) are the 5th to 9th most frequently diagnosed cancer word wide.The most frequent NHL type is diffuse large B-cell lymphoma (DLBCL) which has specificallydefined genetic subtypes. One of them, the so called EZB DLBCL, is affected by somaticmutations of genes coding for proteins involved in the homeostasis of germinal center B cells(EZH2, GNA12, GNA13, S1PR2, ARHGEF1, RHOA). Based on the literature and preliminarydata, we believe that these alterations affect the cortical actin dynamics and related B-cellreceptor (BCR) signaling via modulation of the Wiskott-Aldrich syndrome protein (WASp)function. We propose that this phenomenon represents a potential therapeutic target and thatWASp has additional lymphoma important nuclear function. These associations were notinvestigated before, therefore, we believe that our studies will bring important new informationrelated to critical aspects of lymphomagenesis, and molecular mechanisms in general, as wellas new therapeutic targets for patients with hematological cancers and with autoimmunedisorders. The project aims to investigate 1) how EZB DLBCL recurrent mutations affect the activity ofWASp, actin organization and BCR signaling, 2) the nuclear role of WASp, 3) what are theconsequences of WASp lymphoma specific mutations, 4) lymphoma cells sensitivity to WASptargeting compounds.