| Autor: |
Chiodin, Giorgia, Drennan, Samantha, Martino, Enrica Antonia, Ondrisova, Laura, Henderson, Isla, del Rio, Luis, Tracy, Ian, D’Avola, Annalisa, Parker, Helen, Bonfiglio, Silvia, Scarfo’, Lydia, Sutton, Lesley-Ann, Strefford, Jonathan C., Forster, Jade, Brake, Oliver, Potter, Kathleen N., Sale, Ben, Lanham, Stuart, Mraz, Marek, Ghia, Paolo, Stevenson, Freda K., Forconi, Francesco |
| Zdroj: |
Blood Advances; 20220101, Issue: Preprints |
| Abstrakt: |
Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progress more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 CLL patients (median follow-up of 66 months) and correlated it with pre-treatment sIgM levels and signaling characteristics. Pre-treatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+mobilization (iCa2+), in vitro(r=0.70; p<0.0001). High sIgM levels/signaling strongly correlated with short TTNT (p<0.05), and 36% CLLhighversus 8% CLLlowprogressed to require a new treatment. In vitro,capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pre-therapy sIgM levels (r=-0.68, p=0.01) or iCa2+(r=-0.71, p=0.009). In patients, sIgM-mediated iCa2+and ERK phosphorylation levels were reduced by ibrutinib therapy, but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, while it was minimal when sIgM expression was low (p<0.05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction, able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches. |
| Databáze: |
Supplemental Index |
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