Interactions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, displaying different patterns of stromal cell adhesion and chemotaxis towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. Five-hundred and ninety genes were differently regulated between the cell lines upon adhesion to stromal cells, while 32 genes were similarly regulated in both cell lines. Regulation of B-cell Receptor (BCR) signature genes in adherent cells was specific for JeKo-1. Inhibition of BCR using siRNA or clinically approved inhibitors, Ibrutinib and Acalabrutinib, decreased adhesion of JeKo-1, but not REC-1 cells. Cell surface levels of chemokine receptor CXCR4 were higher in JeKo-1, facilitating migration and adhesion of JeKo-1 but not REC-1 cells. Surface levels of ICAM1 adhesion protein differ for REC-1 and JeKo-1. While ICAM1 played a positive role in adherence of both cell lines to stromal cells, S1PR1 had an inhibitory effect. Our results provide a model framework for further investigation of mechanistic differences in patient-response to new pathway-specific drugs.
SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158).
Introduction Cannabinoid receptors type 1 (CB1) and type 2 (CB2) are tentative treatment-targets in cancer. They are activated by endogenous cannabinoids and by plant cannabinoids such as tetrahydrocannabinol (THC). CB2 is expressed in normal and malignant lymphocytes while CB1 expression is low in normal lymphocytes but high in mantle cell lymphomas and half of cases of chronic lymphocytic leukemia (CLL). Agonists to CB1 and CB2 induce cell death of CB1 or CB2 expressing lymphoid cell lines (Gustafsson, K. et al. Int J Cancer 2008). CB1 and CB2 regulate tissue localization and homing of leukocytes (Muppidi JR, et al. J Exp Med. 2011; Wasik et al., 2014, Oncoscience). We here report the effects of Sativex, which contains a whole-plant mixture of Cannabis sativa with exact proportions of THC and the partial CB1-antagonist cannabidiol (CBD), on patients with indolent B-cell lymphoma. Methods Patients, 18-80 years, with a leukemic indolent B-cell lymphoma without treatment indication, were given a single administration of Sativex, as an oral mucosal spray. The cannabis compound was given at 9 AM and patients were sampled at 0, 2, 4, 6, 24 and 168 hours. They were also sampled at a prior non-treatment day at the same hours of the day to compensate for any circadian rhythms of blood leukocytes. Blood samples were analyzed using blood chemistry and flow cytometry to quantify lymphoma and non-malignant cells. Apoptosis was measured by caspase-3 activation. CB1 and CB2 mRNA levels were quantified using qPCR in enriched lymphoma cells. Results 23 patients were included (Table 1). Maximum tolerated dose was determined to be 7 actuations, containing 18.9mg THC and 17.5mg CBD. This dose was given to 15 patients. Side effects were mostly grade 1 and manageable (Table 2) and all patients could return home at 3 PM. At every time point on the treatment day, there was a significant decrease in lymphocyte counts compared with 0 hours (2 hours, P = 0.004; 4 hours, P < 0.001; 6 hours, P = 0.007), with nadir usually at 4 hours after drug administration (median nadir 0.85 relative to baseline). On the control day, lymphocytes decreased significantly at 4 hours (P = 0.031) and 6 hours (P = 0.026) (median nadir of 0.93 compared to baseline). Changes in clonal B cells were the same as in lymphocytes. The larger median nadir on treatment day was not due to increased cell-death as measured by activated caspase 3. In the non-clonal B-cells, there was no circadian variation during the control day, but a decrease after treatment was detectable (2 hours: P = 0.01; 4 hours: P = 0.034; 6 hours: P = 0.031). T-cells showed no circadian changes and decreased after treatment (4 hours, P = 0.06; 6 hours, P = 0.009). For NK cells, the pattern, regardless of administration of cannabinoids, was a decrease at 6 hours (6 hours no drug, P = 0.051; 6 hours with drug P = 0.013). A week after administration of the cannabis compound, all non-malignant lymphocytes had returned to baseline levels, but the clonal B cells had significantly increased (P = 0.011). Neutrophils increased significantly after treatment (4 hours, P = 0.007; 6 hours, P = 0.005) whereas platelets decreased at 2 hours (P = 0.003). CB2 mRNA was expressed in all lymphomas and 17/23 lymphomas expressed CB1 mRNA. There was no correlation between baseline levels of CB2, CB1 or plasma concentrations of THC and CBD to nadir of lymphocytes (all P > 0.4). The cannabis compound reduced lymphocyte levels both in CB1-positive and CB1-negative lymphoma (CB1+, P = 0.028; CB1-, P = 0.013). Conclusion This study demonstrates that it is safe to administrate a single dose of Sativex to elderly patients with indolent B-cell lymphoma with regards to adverse events. We show that the cannabis compound quickly reduces lymphoma cell numbers in peripheral blood. There was no evidence of activation of caspase 3; this suggests that the reduction of lymphoma cells in blood might be due to redistribution from blood rather than apoptosis. We have also detected an apparent circadian rhythm of the peripheral numbers of malignant lymphocytes. Our findings suggest that the drug might promote homing of lymphoma cells from blood into secondary lymphoid organs where they receive pro-survival signals. Therefore, this cannabinoid compound should be used with caution in patients with indolent leukemic lymphomas. Further studies are needed to dissect the signaling pathways affected by cannabinoids in B-cell lymphoma. Disclosures Wahlin: Roche and Gilead: Consultancy. OffLabel Disclosure: Sativex is an oromucosal spray containing whole plant Cannabis sativa. In Europe is is registred for use against spasticity caused by multiple sclerosis.
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