VLA-4 activation mechanisms in chronic lymphocytic leukemia: clinical relevance in the new drug era

The integrin VLA-4 is expressed at high levels in about 40% of chronic lymphocytic leukemia (CLL) cases and represents a negative prognostic factor. VLA-4 can efficiently bind its ligands when activated by several mechanisms, including those mediated by the B cell receptor (BCR). The purpose of this project is to challenge these findings in a clinical setting. To do so, the VLA-4 activation state, as measured in CLL cells either at constitutive level or induced by BCR triggering, will be tested for its power to predict response and/or development of resistance to the BCR inhibitor Ibrutinib in two different clinical trials. The effectiveness to impair the VLA-4 activation state in-vitro will be also used to test the potency of the main clinical grade BCR inhibitors (ibrutinib, fosfamatinib,idelalisib), thus providing the biological basis to design clinical trials combining different BCR inhibitors for VLA-4 expressing CLL.

Duration: 2018-2020

Donor/funding programme:

“Ministero della Salute”
Bando Ricerca Finalizzata anno 2016

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Dimitar Efremov Molecular Hematology, ICGEB Trieste, Italy

IRCCS CRO Aviano, Italy

University of Texas, USA