Immunomodulatory drugs (IMiDs)- or cereblon E3 ligase modulator (CELMoD)-induced growth suppression of Adult T-Cell Lymphoma/Leukemia (ATL) cells and the intrinsic rolls of cereblon for down-regulation of target proteins and their down-stream effectors
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PROVIDER: PRJNA912679 | ENA |
REPOSITORIES: ENA
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Project description:Adult T-cell lymphoma/leukemia (ATL) is an aggressive subtype of leukemia/lymphoma caused by human T-cell leukemia virus type-1 (HTLV-1) and existing chemotherapy for ATL remains with extremely poor prognosis. Therefore, more effective therapeutic options are urgent needs for this disease. Since recent two clinical studies proved promising curability of Lenalidomide (LEN, a second-generation immunomodulatory drug [IMiDs]) for ATL patients, we investigated the direct growth-inhibitory machineries of LEN on ATL cells. Among 13 ATL-related cell lines, Hut102 and TL-Om1 exhibited best response to LEN treatment and LEN-induced functional modulation of E3-ubiquitin ligase cereblon (CRBN) induced degradation of hematopoietic-specific ikaros-family transcription factors IKZF1 and IKZF3 followed by suppression of their down-stream effectors IRF4 and c-Myc (both have been implied to promote ATL cell malignancy). Additionally, Hut102 and TL-Om1 displayed impaired expression of IKZF2 (deletion in HuT102 and altered translational variants in TL-Om1). LEN-induced growth inhibition to these two cell-lines seemed to be attributed to functional deprivation of all IKZF1/2/3. While CRBN-knockdown (KD) in HuT102 imposed LEN-resistance, IKZF2-KD in LEN-resistant ED40515 induced LEN sensitivity. DNA microarray analysis on LEN-treated HuT102 and OATL4 (LEN-resistant) displayed distinct LEN-responding transcriptional profiles; restoration of immune competency and oncogenic growth promotion respectively. Oral administration of LEN to HuT102-xenographted SCID mice demonstrated significant reduction of tumor mass. Finally, a novel form of IMiDs or cereblon modulator (CELMoD), iberdomide (IBE) exerted deeper and wider range of growth suppression to ATL cells including IKZF2 down regulation. Altogether, these findings strongly indicate the therapeutic advantages of IMiDs or CELMoD against ATL.
2024-02-15 | GSE221056 | GEO
Project description:Adult T-cell lymphoma/leukemia (ATL) is an aggressive subtype of leukemia/lymphoma caused by human T-cell leukemia virus type-1 (HTLV-1) and existing chemotherapy for ATL remains with extremely poor prognosis. Therefore, more effective therapeutic options are urgent needs for this disease. Since recent two clinical studies proved promising curability of Lenalidomide (LEN, a second-generation immunomodulatory drug [IMiDs]) for ATL patients, we investigated the direct growth-inhibitory machineries of LEN on ATL cells. Among 13 ATL-related cell lines, Hut102 and TL-Om1 exhibited best response to LEN treatment and LEN-induced functional modulation of E3-ubiquitin ligase cereblon (CRBN) induced degradation of hematopoietic-specific ikaros-family transcription factors IKZF1 and IKZF3 followed by suppression of their down-stream effectors IRF4 and c-Myc (both have been implied to promote ATL cell malignancy). Additionally, Hut102 and TL-Om1 displayed impaired expression of IKZF2 (deletion in HuT102 and altered translational variants in TL-Om1). LEN-induced growth inhibition to these two cell-lines seemed to be attributed to functional deprivation of all IKZF1/2/3. While CRBN-knockdown (KD) in HuT102 imposed LEN-resistance, IKZF2-KD in LEN-resistant ED40515 induced LEN sensitivity. DNA microarray analysis on LEN-treated HuT102 and OATL4 (LEN-resistant) displayed distinct LEN-responding transcriptional profiles; restoration of immune competency and oncogenic growth promotion respectively. Oral administration of LEN to HuT102-xenographted SCID mice demonstrated significant reduction of tumor mass. Finally, a novel form of IMiDs or cereblon modulator (CELMoD), iberdomide (IBE) exerted deeper and wider range of growth suppression to ATL cells including IKZF2 down regulation. Altogether, these findings strongly indicate the therapeutic advantages of IMiDs or CELMoD against ATL.
2024-02-15 | GSE221062 | GEO
Project description:Immunomodulatory drugs (IMiDs)- or cereblon E3 ligase modulator (CELMoD)-induced growth suppression of Adult T-Cell Lymphoma/Leukemia (ATL) cells and the intrinsic rolls of cereblon for down-regulation of target proteins and their down-stream effectors II
| PRJNA912688 | ENA
Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included 15 samples from multiple myeloma cell lines.
2011-09-30 | E-GEOD-31421 | biostudies-arrayexpress
Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included two isogenic MM1.S cell lines, which differ in the sensibiligy to lenalidomide. We included MM1.S and MM1.S res, which were sensitive and resistant to lenalidomide, respectively.
2011-09-30 | E-GEOD-31451 | biostudies-arrayexpress
Project description:Abstract: Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 18 ATL patient samples using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared to normal lymphocytes. Several unique genes were identified that were overexpressed in leukemia cells including TNFSF11, RGS13, MAFb, CSPG2, C/EBPalpha and TCF4. 200 of the most highly overexpressed ATL genes were analyzed by the PathwayStudio 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, PCNA and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells wi BIRC5 shRNA decreased BIRC5 exprression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies. Keywords: disease state analysis
2009-02-01 | GSE14317 | GEO
Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy.
2011-10-01 | GSE31451 | GEO
Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy.
2011-10-01 | GSE31421 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE31421: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling] GSE31451: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [aCGH] Refer to individual Series
2011-09-30 | E-GEOD-31452 | biostudies-arrayexpress
Project description:To identify chromosomal alterations in ATL, SNP array analyses were performed in 19 leukemia cell samples from ATL patients and 9 ATL-related cell lines. ATL displayed complex chromosomal abnormalities, but it contained recurrent chromosomal amplification and deletion, including 14q11 and 14q32, which may be associated with the development of ATL. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved peripheral blood samples and from cell line samples.
2017-06-06 | GSE99667 | GEO