期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 215, 期 2, 页码 681-697出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171288
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资金
- Associazione Italiana Ricerca Cancro [IG-17622]
- Progetto Giovani Ricercatori [GR-2011-02347441, GR-2011-02346826, GR-2011-02351370]
- Ministero della Salute (Rome, Italy)
- Ricerca clinica, traslazionale, di base, epidemiologica e organizzativa, Regione Friuli Venezia Giulia (Linfo-Check Project), Trieste, Italy
- Associazione Italiana contro le Leucemie, Linfomi e Mielomi, Venezia Section, Pramaggiore Group, Italy
- Fondazione per la Vita di Pordenone, Italy
- 5x1000 Intramural Program, Centro di Riferimento Oncologico, Aviano, Italy
- intramural research program of the National, Heart, Lung, and Blood Institute, National Institutes of Health
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.
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