The Expression of Sphingosine-1 Phosphate Receptor-1 in Chronic Lymphocytic Leukemia Cells Is Impaired by Tumor Microenvironmental Signals and Enhanced by Piceatannol and R406

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of clonal B lymphocytes. Proliferation occurs in lymphoid tissues upon interaction of leukemic cells with a supportive microenvironment. Therefore, the mobilization of tissue-resident CLL cells into the circulation is a useful therapeutic strategy to minimize the reservoir of tumor cells within survival niches. Because the exit of normal lymphocytes from lymphoid tissues depends on the presence of sphingosine-1 phosphate (S1P) and the regulated expression of S1P receptor-1 (S1PR1), we investigated whether the expression and function of S1PR1 can be modulated by key microenvironment signals. We found that activation of CLL cells with CXCL12, fibroblast CD40L+, BCR cross-linking, or autologous nurse-like cells reduces their S1PR1 expression and the migratory response toward S1P. Moreover, we found that S1PR1 expression was reduced in the proliferative/activated subset of leukemic cells compared with the quiescent subset from the same patient. Similarly, bone marrow–resident CLL cells expressing high levels of the activation marker CD38 showed a lower expression of S1PR1 compared with CD38low counterparts. Finally, given that treatment with BCR-associated kinase inhibitors induces a transient redistribution of leukemic cells from lymphoid tissues to circulation, we studied the effect of the Syk inhibitors piceatannol and R406 on S1PR1 expression and function. We found that they enhance S1PR1 expression in CLL cells and their migratory response toward S1P. Based on our results, we suggest that the regulated expression of S1PR1 might modulate the egress of the leukemic clone from lymphoid tissues.

Sphingosine kinase 1 participates in the activation, proliferation and survival of chronic lymphocytic leukemia cells

“…Malignant B cells from CLL patients mainly receive advantageous signals in lymphoid tissues, where the supportive microenvironment and B cell receptor (BCR) signaling promote their activation and proliferation, modulate cell adhesion and migration and protect CLL cells from spontaneous and drug-induced apoptosis. 5 We have previously reported that CLL cells activated by signals from the supportive microenvironment transiently impair the expression of S1PR1, 6 in a process that may extend the residency of the leukemic clone within the survival niches of lymphoid tissues. In the study herein we wanted to determine whether the activation of CLL cells has any influence on SK1/S1PL ratios.…”

“…Patients number 1, 2 and 14 in the Online Supplementary Table S1 correspond to Patients number 39, 40 and 38, respectively, from our previous paper. 6 (F) Bone marrow mononuclear cells from 3 CLL patients were segregated by CD38 expression as previously detailed. 6 Total RNA was purified from the CD19 + CD38 high fraction and from the CD19 + CD38 low/negative fraction.…”

“…6 (F) Bone marrow mononuclear cells from 3 CLL patients were segregated by CD38 expression as previously detailed. 6 Total RNA was purified from the CD19 + CD38 high fraction and from the CD19 + CD38 low/negative fraction. SK1 and S1PL mRNA were evaluated as described above.…”

“…4 Carmen Stanganelli, 5 Irma Slavutsky, 6 María Cabrejo, 7 Horacio Fernández-Grecco, 7 Raimundo Fernando Bezares, 8 Santiago Cranco, 9 Rubén Ángel Burgos, 9 Julio César Sánchez-Ávalos, 9 Pablo Oppezzo, 10 Mirta Giordano 1,3 and Romina Gamberale …”

“…Thus, the possibility exists that microenvironment signals from lymphoid tissues, by increasing SK1/S1PL ratios in leukemic CLL cells, favors S1P production. Exported S1P can then bind S1PRs, reduce S1PR1 expression 6 and transduce stimulating signals to the leukemic clone.…”