Cell-autonomous and cell-extrinsic BCR interactions as therapeutic targets in chronic lymphocytic leukemia

Funded by the Italian Association for Cancer Research under AIRC Investigator Grant. The project has awarded to the Molecular Hematology group, headed by Dimitar Efremov.

The project received EUR 252K funding and is exclusive to the ICGEB.

Recent studies have shown that the B cell receptor (BCR) pathway is activated in chronic lymphocytic leukemia (CLL) B cells by two types of interactions. The first type are interactions with low-affinity external autoantigens, which are typically recognized by the leukemic BCRs from patients with aggressive/IGHV-unmutated CLL. The second type are cell-autonomous BCR-BCR interactions, which are a feature of leukemic BCRs from patients with both aggressive/IGHV-unmutated and indolent/IGHV-mutated CLL.

In a recent study we showed that both types of interactions are positively selected during leukemia development in the Em-TCL1 transgenic mouse model of CLL, suggesting that they have independent roles in the pathogenesis of the disease.

The main objective of this project is to characterize the composition of the BCR microsignalosomes and the downstream signaling pathways that are activated by the different BCR interactions in murine and human CLL B cells. Characterization of these signals at the molecular level is important because it may lead to the identification of novel biomarkers to predict disease progression as well as novel targets for CLL treatment.

Duration: 2017-2019

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