The role of CD44 in the pathophysiology of chronic lymphocytic leukemia

CD44 interactions with hyaluronan (HA) play a key role in various malignancies, supporting tumor cell migration, adhesion, and survival. In contrast to solid tumors, the expression of CD44 standard and variant forms and their functional interplay with HA is less understood in hematological malignancies. Chronic lymphocytic leukemia (CLL) is a highly abundant Bcell malignancy with a well coordinated balance between cell cycle-arrest and proliferation of tumor subpopulations.The long-term survival and proliferation of CLL cells requires their dynamic interactions with stromal and immune cells in lymphoid organs. Interactions of HA with CD44 and HA-mediated motility receptor (RHAMM) contribute to CLL cell localization, and hence CLL pathophysiology, by shaping homing, interstitial migration, and adhesion of the tumor cells. CD44 can complex with key prognostic factors of CLL, particularly CD38 and CD49d, bridging the gap between prognosis and cellular function. Here, we review the current evidence for the individual and associated contributions of CD44 to CLL pathophysiology, the dynamic functional regulation of CD44 upon CLL cell activation, and possible therapeutic strategies targeting CD44 in CLL

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

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