The effect of FK506 on transforming growth factor   signaling and apoptosis in chronic lymphocytic leukemia B cells

Romano, Simona; Mallardo, Maria; Chiurazzi, Federico; Bisogni, Rita; Dilhas, Anna; Liuzzi, Raffaele; Compare, Giovanna; Romano, Maria

doi:10.3324/haematol.12402

Cited by 25 publications

(20 citation statements)

References 33 publications

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“…(24) Interestingly, we identified changes in the transcriptional program of EPBLs associated with apoptosis after dasatinib exposure. Among the genes that underwent downregulation were SYK, which is implicated in lymphocyte signaling and survival and for which inhibitors are currently under clinical study in CLL,(25) FK506BP, which modulates the apoptotic signal of TGF-β in CLL,(26) EGR1, whose expression is associated with survival in CLL(27), NLR Card 3, which is downregulated 6 hrs following T-lymphocyte stimulation(28), and Notch 2, which similarly undergoes downregulation in CLL cells treated with proteasome inhibitors. (29) In contrast, genes which were upregulated included GNAS1, whose T393C polymorphism has been correlated with prognosis in CLL in one study(30) but not in another.…”

Section: Discussionmentioning

confidence: 99%

Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Amrein

Attar

Takvorian

et al. 2011

Clinical Cancer Research

109

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Purpose CLL cells treated with dasatinib in vitro undergo apoptosis via inhibition of Lyn kinase. Thus, in this study we tested the activity of dasatinib in patients with relapsed CLL. Experimental Design Patients were eligible for this phase 2 trial if they had documented CLL/SLL and had failed at least one prior therapy with a fludarabine-containing regimen and if they required therapy according to NCI-WG criteria. The starting dose of dasatinib was 140 mg daily. Results Fifteen patients were enrolled, with a median age of 59 and a median of 3 prior regimens. All patients had received fludarabine, and 5 were fludarabine-refractory. Eleven of the 15 (73%) had high risk del(11q) or del(17p) cytogenetics. The primary toxicity was myelosuppression, with grade 3 or 4 neutropenia and thrombocytopenia in 10 and 6 patients, respectively. Partial responses by NCI-WG criteria were achieved in 3 of the 15 patients (20%; 90% CI 6–44). Among the remaining 12 patients, 5 had nodal responses by physical exam, and 1 patient had a nodal and lymphocyte response but with severe myelosuppression. Pharmacodynamic studies indicated apoptosis in peripheral blood CLL cells within 3–6 hours after dasatinib administration, associated with downregulation of syk mRNA. Conclusions Dasatinib as a single agent has activity in relapsed and refractory CLL.

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Section: Discussionmentioning

confidence: 99%

Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Amrein

Attar

Takvorian

et al. 2011

Clinical Cancer Research

109

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“…10 Figure 1 shows representative results of the effect of FKBP51 gene silencing in the SAN melanoma cell line. The downmodulating effect of FKBP51 siRNA was specific because it could not be reproduced by a siRNA for FKBP12 17 ( Figure 1a). A clonogenic assay was performed using cells transfected with FKBP51 siRNA, non-silencing (NS) RNA, or nothing.…”

Section: Fkbp51 Downmodulation Sensitizes Melanoma Cells Tomentioning

confidence: 99%

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

et al. 2009

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FK506-binding protein 51 (FKBP51) is an immunophilin with isomerase activity, which performs important biological functions in the cell. It has recently been involved in the apoptosis resistance of malignant melanoma. The aim of this study was to investigate the possible role of FKBP51 in the control of response to ionizing radiation (Rx) in malignant melanoma. FKBP51-silenced cells showed reduced clonogenic potential after irradiation compared with non-silenced cells. After Rx, we observed apoptosis in FKBP51-silenced cells and autophagy in non-silenced cells. The FKBP51-controlled radioresistance mechanism involves NF-jB. FKBP51 was required for the activation of Rx-induced NF-jB, which in turn inhibited apoptosis by stimulating X-linked inhibitor of apoptosis protein and promoting authophagy-mediated Bax degradation. Using a tumor-xenograft mouse model, the in vivo pretreatment of tumors with FKBP51-siRNA provoked massive apoptosis after irradiation. Immunohistochemical analysis of 10 normal skin samples and 80 malignant cutaneous melanomas showed that FKBP51 is a marker of melanocyte malignancy, correlating with vertical growth phase and lesion thickness. Finally, we provide evidence that FKBP51 targeting radiosensitizes cancer stem/initiating cells. In conclusion, our study identifies a possible molecular target for radiosensitizing therapeutic strategies against malignant melanoma.

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“…Most of the decreased miRNAs are related to the immunosuppressive functions of FK506, including inhibition of the well-known cytokines, such as interleukin 2 and CD40 [12,13], and the regulation of calcium/calmodulin dependent kinases [14-16] and NFATs [17], which are the intracellular transcription factors. FK506 is known to release FKBP12, which is bound to the transforming growth factor (TGF)-β receptor in a chronic lymphocytic leukemia B cell, and phosphorylates and activates the receptor, thereby causing phosphorylation of Smad and leading to apoptosis [18,19]. In a smooth muscle cell, however, it was found that the activation of the TGF-β receptor by FK506 stimulates cell growth [1,18].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA profiling of tacrolimus-stimulated Jurkat human T lympocytes

2013

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PurposeThis study investigated the Jurkat T cell line expresses cytotoxicity when treated with different concentrations of FK506, and analyzed the expression pattern of microRNA when stimulated by FK506 using the microRNAs microarray, as well as the expression pattern of a gene that is related to the differentiation, activation and proliferation of T cells after being affected by the change of microRNAs.MethodsTo investigate the effects of FK506 on microRNA expression, we purified total RNA of Jurkat cells treated with 20 µM FK506 for 72 hours and used to analyze microRNA profiling by using Agilent's chip.ResultsThese results demonstrated that treatment with FK506 markedly induced the down-regulation of 20 microRNAs as well as the up-regulation of 20 microRNAs in a time-dependent manner. The genes that down-regulated by FK506 include let-7a*, miR-20a*, and miR-487a. Otherwise miR-202, miR-485-5p, and miR-518c* are gradually up-regulated in expression. Sanger Institute and DAVIDs bioinformatics indicated that microRNAs regulated the several transcriptomes including nuclear factor of activated T cell-related, T cell receptor/interleukin-2 signaling, and Ca2+-calmodulin-dependent phosphatase calcineurin pathways.ConclusionAs a result of treating FK506 to a Jurkat cell line and running the microRNA microarray, it was found that FK506 not only took part in the suppression of T cell proliferation/activation by inhibiting calcineurin in Jurkat apoptosis, but also affected the microRNAs that are involved in the regulation of various signal transduction pathways.

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The effect of FK506 on transforming growth factor signaling and apoptosis in chronic lymphocytic leukemia B cells

Cited by 25 publications

References 33 publications

Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

MicroRNA profiling of tacrolimus-stimulated Jurkat human T lympocytes

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