Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia.
Erika TissinoDania BenedettiSarah E M HermanElisa Ten HackenInhye E AhnKari G RabeFrancesca Maria RossiMichele Dal BoPietro BulianRiccardo BombenElisabeth BayerAndrea HärzschelJulia Christine GutjahrMassimiliano PostorinoEnrico SantinelliAyed O AyedFrancesco ZajaAnnalisa ChiarenzaGabriele PozzatoAlexandre ChigaevLarry A SklarJan A BurgerAlessandra FerrajoliTait D ShanafeltAdrian WiestnerGiovanni Del PoetaTanja Nicole HartmannValter GatteiAntonella ZucchettoPublished in: The Journal of experimental medicine (2018)
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.
Keyphrases
- chronic lymphocytic leukemia
- tyrosine kinase
- epidermal growth factor receptor
- acute lymphoblastic leukemia
- cell adhesion
- induced apoptosis
- poor prognosis
- nk cells
- free survival
- newly diagnosed
- end stage renal disease
- lymph node
- chronic kidney disease
- oxidative stress
- genome wide
- cell cycle arrest
- squamous cell carcinoma
- gene expression
- radiation therapy
- signaling pathway
- binding protein
- dna methylation