Abstract
Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients
Highlights
Chronic lymphocytic leukemia (CLL) is one of the most common B-cell malignancies in adults, characterized by an accumulation of monoclonal CD5+ mature B-cells in lymphoid tissues and peripheral blood (PB)
Clonal expansion and invasive migration typically lead to CLL cell involvement in the lymph nodes (LNs), spleen and bone marrow (BM)
The CD68+ CD163+ nurse-like cells (NLC) subset of macrophage cells have been described as tumorassociated macrophages in CLL and are found in various tumoral niches (LNs, spleen and BM)
Summary
Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients. CD14+ monocytes did not express the NLC marker CD163 at the time of blood sampling, similar to what has been shown in untreated patients.10 This suggested that ibrutinib does not induce the egress of fully differentiated NLC from niches, leaving a potential capacity for their interaction with residual CLL cells. In the absence of NLC, CLL cells cultivated from ibrutinib-treated patients were more sensitive to apoptosis compared with CLL cells from untreated patients (Figure 1d) These results show that ibrutinib treatment does not alter the capacity of CLL cells to induce monocyte differentiation into NLC, suggesting that this process is BTK-independent. To make sure that the in vitro data were relevant, drug concentrations were chosen according to the maximum achievable concentrations reported in clinical trials At these selected doses, apoptosis was detectable for all antileukemic agents when CLL cells were treated without NLC, with the expected inter-patient heterogeneity (Figure 2a). The chemoprotective effect induced by NLC in ibrutinib-treated patients was lost upon cotreatment with bendamustin (Figure 2d)
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