Lenalidomide Stabilizes the Erythropoietin Receptor by Inhibiting the E3 Ubiquitin Ligase RNF41

Basiorka, Ashley A.; McGraw, Kathy L.; Ceuninck, Leentje De; Griner, Lori N.; Zhang, Ling; Clark, Justine; Cáceres, Gisela; Sokol, Lubomir; Komrokji, Rami; Reuther, Gary W.; Wei, Sheng; Tavernier, Jan; List, Alan F.

doi:10.1158/0008-5472.can-15-1756

Cited by 29 publications

(21 citation statements)

References 30 publications

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“…Indeed, β-Clec16a KO islets had impaired clearance of Mfn2 and Parkin following cytokine exposure, consistent with Clec16a control of cytokine-induced mitophagy ( Figures 5A-B). Similarly, treatment of islets from mtKeima mice with lenalidomide, a pharmacologic inhibitor of the CLEC16A-mediated mitophagy pathway (11,44), impaired cytokine-induced mitophagy ( Figure 5C).…”

Section: Clec16a Regulates Cytokine-induced Mitophagy In Rodent and Hmentioning

confidence: 86%

Mitophagy protects beta cells from inflammatory damage in diabetes

Sidarala

Pearson

Parekh

et al. 2020

Preprint

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Inflammatory damage contributes to β-cell failure in type 1 and 2 diabetes (T1D and T2D).Mitochondria are damaged by inflammatory signaling in β-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent β-cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic pro-inflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient β-cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased β-cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human β-cell apoptosis. Thus, mitophagy promotes β-cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent βcell failure in diabetes and may be beneficial in other inflammatory conditions.

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Section: Clec16a Regulates Cytokine-induced Mitophagy In Rodent and Hmentioning

confidence: 86%

Mitophagy protects beta cells from inflammatory damage in diabetes

Sidarala

Pearson

Parekh

et al. 2020

Preprint

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“…Lenalidomide is an immunomodulating drug that is currently being used in patients diagnosed with myelodysplastic syndromes (MDSs) who also bear a deletion in the long arm of chromosome 5 [del(5q)] (1). Indeed, in these cases of low‐risk MDS, lenalidomide may suppress the del (5q) clone and restore normal erythropoiesis (2, 3). Moreover, in lenalidomide‐sensitive del(5q) cell lines, Akt phosphorylation is inhibited and cell cycle arrest is detected (4).…”

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confidence: 99%

Nuclear translocation of PKC‐ α is associated with cell cycle arrest and erythroid differentiation in myelodysplastic syndromes (MDSs)

et al. 2018

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PI-PLCβ1 is involved in cell proliferation, differentiation, and myelodysplastic syndrome (MDS) pathogenesis. Moreover, the increased activity of PI-PLCβ1 reduces the expression of PKC-α, which, in turn, delays the cell proliferation and is linked to erythropoiesis. Lenalidomide is currently used in low-risk patients with MDS and del(5q), where it can suppress the del(5q) clone and restore normal erythropoiesis. In this study, we analyzed the effect of lenalidomide on 16 patients with low-risk del(5q) MDS, as well as del(5q) and non-del(5q) hematopoietic cell lines, mainly focusing on erythropoiesis, cell cycle, and PI-PLCβ1/PKC-α signaling. Overall, 11 patients were evaluated clinically, and 10 (90%) had favorable responses; the remaining case had a stable disease. At a molecular level, both responder patients and del(5q) cells showed a specific induction of erythropoiesis, with a reduced γ/β-globin ratio, an increase in glycophorin A, and a nuclear translocation of PKC-α. Moreover, lenalidomide could induce a selective G/G arrest of the cell cycle in del(5q) cells, slowing down the rate proliferation in those cells. Altogether, our results could not only better explain the role of PI-PLCβ1/PKC-α signaling in erythropoiesis but also lead to a better comprehension of the lenalidomide effect on del(5q) MDS and pave the way to innovative, targeted therapies.-Poli, A., Ratti, S., Finelli, C., Mongiorgi, S., Clissa, C., Lonetti, A., Cappellini, A., Catozzi, A., Barraco, M., Suh, P.-G., Manzoli, L., McCubrey, J. A., Cocco, L., Follo, M. Y. Nuclear translocation of PKC-α is associated with cell cycle arrest and erythroid differentiation in myelodysplastic syndromes (MDSs).

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“…It is not known if this is also true for the plasma cells, but may open for a combinatorial treatment strategy between lenalidomide and EPO [18]. …”

Section: Discussionmentioning

confidence: 99%

Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro

et al. 2016

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BackgroundMultiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO)-receptor (EPOR) signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated.MethodsMyeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this study. Transcript levels were analysed by quantitative PCR and cell surface levels of EPOR in primary cells by flow cytometry. Knockdown of EPOR by short interfering RNA was used to show specific EPOR signaling in the myeloma cell line INA-6. Flow cytometry was used to assess viability in primary cells treated with EPO in the presence and absence of neutralizing anti-EPOR antibodies. Gene expression data for total therapy 2 (TT2), total therapy 3A (TT3A) trials and APEX 039 and 040 were retrieved from NIH GEO omnibus and EBI ArrayExpress.ResultsWe show that the EPOR is expressed in myeloma cell lines and in primary myeloma cells both at the mRNA and protein level. Exposure to recombinant human EPO (rhEPO) reduced viability of INA-6 myeloma cell line and of primary myeloma cells. This effect could be partially reversed by neutralizing antibodies against EPOR. In INA-6 cells and primary myeloma cells, janus kinase 2 (JAK-2) and extracellular signal regulated kinase 1 and 2 (ERK-1/2) were phosphorylated by rhEPO treatment. Knockdown of EPOR expression in INA-6 cells reduced rhEPO-induced phospo-JAK-2 and phospho-ERK-1/2. Co-cultures of primary myeloma cells with bone marrow-derived stroma cells did not protect the myeloma cells from rhEPO-induced cell death. In four different clinical trials, survival data linked to gene expression analysis indicated that high levels of EPOR mRNA were associated with better survival.ConclusionsOur results demonstrate for the first time active EPOR signaling in malignant plasma cells. EPO-mediated EPOR signaling reduced the viability of myeloma cell lines and of malignant primary plasma cells in vitro. Our results encourage further studies to investigate the importance of EPO/EPOR in multiple myeloma progression and treatment.Trial registration[Trial registration number for Total Therapy (TT) 2: NCT00083551 and TT3: NCT00081939].

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Lenalidomide Stabilizes the Erythropoietin Receptor by Inhibiting the E3 Ubiquitin Ligase RNF41

Cited by 29 publications

References 30 publications

Mitophagy protects beta cells from inflammatory damage in diabetes

Mitophagy protects beta cells from inflammatory damage in diabetes

Nuclear translocation of PKC‐ α is associated with cell cycle arrest and erythroid differentiation in myelodysplastic syndromes (MDSs)

Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro

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