Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly

Gandhi, Anita K.; Kang, Jian; Naziruddin, S.; Parton, Anastasia; Schäfer, Peter; Stirling, David I.

doi:10.1016/j.leukres.2006.01.010

Cited by 86 publications

(74 citation statements)

References 38 publications

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“…Enhanced sensitivity of cells with the del(5q) to lenalidomide also has been observed in certain cell lines, in which the effects are mainly restricted to growth inhibition and cell cycle arrest (35). Most recently, Verhelle et al (36) showed that lenalidomide inhibits the proliferation of malignant B cells while expanding normal CD34 ϩ progenitor cells.…”

Section: Discussionmentioning

confidence: 94%

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

Pellagatti

Jädersten

Forsblom

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

221

167

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Myelodysplastic syndromes (MDSs) are a group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral blood cytopenias. Lenalidomide has dramatic therapeutic effects in patients with low-risk MDS and a chromosome 5q31 deletion, resulting in complete cytogenetic remission in >60% of patients. The molecular basis of this remarkable drug response is unknown. To gain insight into the molecular targets of lenalidomide we investigated its in vitro effects on growth, maturation, and global gene expression in isolated erythroblast cultures from MDS patients with del(5)(q31). Lenalidomide inhibited growth of differentiating del(5q) erythroblasts but did not affect cytogenetically normal cells. Moreover, lenalidomide significantly influenced the pattern of gene expression in del(5q) intermediate erythroblasts, with the VSIG4, PPIC, TPBG, activin A, and SPARC genes up-regulated by >2-fold in all samples and many genes involved in erythropoiesis, including HBA2, GYPA, and KLF1, down-regulated in most samples. Activin A, one of the most significant differentially expressed genes between lenalidomide-treated cells from MDS patients and healthy controls, has pleiotropic functions, including apoptosis of hematopoietic cells. Up-regulation and increased protein expression of the tumor suppressor gene SPARC is of particular interest because it is antiproliferative, antiadhesive, and antiangiogenic and is located at 5q31-q32, within the commonly deleted region in MDS 5q؊ syndrome. We conclude that lenalidomide inhibits growth of del(5q) erythroid progenitors and that the up-regulation of SPARC and activin A may underlie the potent effects of lenalidomide in MDS with del(5)(q31). SPARC may play a role in the pathogenesis of the 5q؊ syndrome.gene expression profiling ͉ myelodysplastic syndromes ͉ microarray ͉ erythropoiesis ͉ osteonectin

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Section: Discussionmentioning

confidence: 94%

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

Pellagatti

Jädersten

Forsblom

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

221

167

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“…12 Nuclear factor-kB a key transcriptional factor regulating the transcription of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein is also inhibited by IMiDs. 8,13,14 Further, IMiDs activate mitochondrial pathways that lead to release of proapoptotic proteins, such as cytochrome c and Smac that help overcome the effects of other antiapoptotic effectors. 15 As dexamethasone triggers release of Smac from the mitochondria but not cytochrome c, its combination with lenalidomide or other IMiDs augments the activity of these agents.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Treatment of plasma cell dyscrasias with lenalidomide

Dimopoulos

Rajkumar

2008

Leukemia

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Lenalidomide is an immunomodulatory drug, structurally related to thalidomide, with pleiotropic activity including antiangiogenic and antineoplastic properties. It is the product of advances in our understanding of the biology of myeloma cells, their interactions with the microenvironment and of the underlying molecular pathways. In preclinical and clinical studies, lenalidomide was more potent and less toxic than thalidomide. Subsequent phase II and III studies confirmed the activity of lenalidomide either as a single agent or in combination with dexamethasone in relapsed or refractory myeloma patients, whereas combinations with chemotherapy induce high response rates and durable remissions. Lenalidomide has been used successfully as an upfront treatment either with high or low dose dexamethasone or with melphalan and prednisone, resulting in high overall response and complete response rates and excellent 1-year survival. Lenalidomide causes less neuropathy than thalidomide; however, the risk of thromboembolism is high, especially in patients treated with lenalidomide and steroids. In this review, we summarize the mechanisms of action, toxicity and clinical activity, and the current role of lenalidomide in patients with multiple myeloma or other related plasma cell disorders.

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“…Lenalidomide (Revlimid) and pomalidomide are IMiDs immunomodulatory compounds developed by Celgene Corp. that possess multiple cellular activities including direct inhibition of hematopoietic tumor growth, immunomodulation via T-cell and natural killer cell stimulation, enhancement of erythropoiesis, and microenvironmental effects such as antiangiogenic activity (1)(2)(3)(4)(5)(6). These compounds have negative effects on hematopoietic tumor cell proliferation and positive effects on CD34 + cell expansion (1)(2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

“…These compounds have negative effects on hematopoietic tumor cell proliferation and positive effects on CD34 + cell expansion (1)(2)(3)(4)(5)(6). Lenalidomide has been approved by the Food and Drug Administration for the treatment of patients with transfusiondependent anemia due to low-risk or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy (7,8).…”

Section: Introductionmentioning

confidence: 99%

Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism

Escoubet-Lozach¹,

Lin²,

Jensen-Pergakes³

et al. 2009

Cancer Research

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158

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Lenalidomide and pomalidomide have both been evaluated clinically for their properties as anticancer agents, with lenalidomide being available commercially. We previously reported that both compounds cause cell cycle arrest in Burkitt's lymphoma and multiple myeloma cell lines by increasing the level of p21 WAF-1 expression. In the present study, we unravel the molecular mechanism responsible for p21 WAF-1 up-regulation using Namalwa cells as a human lymphoma model. We show that the increase of p21 WAF-1 expression is regulated at the transcriptional level through a mechanism independent of p53. Using a combination of approaches, we show that several GC-rich binding transcription factors are involved in pomalidomide-mediated upregulation of p21 WAF-1 . Furthermore, we report that p21 WAF-1 up-regulation is associated with a switch from methylated to acetylated histone H3 on p21 WAF-1 promoter. Interestingly, lysine-specific demethylase-1 (LSD1) silencing reduced both pomalidomide and lenalidomide up-regulation of p21 WAF-1 , suggesting that this histone demethylase is involved in the priming of the p21 WAF-1 promoter. Based on our findings, we propose a model in which pomalidomide and lenalidomide modify the chromatin structure of the p21 WAF-1 promoter through demethylation and acetylation of H3K9. This effect, mediated via LSD1, provides GC-rich binding transcription factors better access to DNA, followed by recruitment of RNA polymerase II and transcription activation. Taken together, our results provide new insights on the mechanism of action of pomalidomide and lenalidomide in the regulation of gene transcription, imply possible efficacy in p53 mutated and deleted cancer, and suggest new potential clinical uses as an epigenetic therapy.

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Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly

Cited by 86 publications

References 38 publications

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

Treatment of plasma cell dyscrasias with lenalidomide

Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism

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