ArticleNature medicine2016
A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes.
Article in Nature medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.
- The Coming of Age of Preclinical Models of MDS.Frontiers in oncology · 2022Pooled it
- TP-0903 Suppresses Aurora A-PLK1 Signaling to Inhibit Proliferation of a Myelodysplastic Syndrome-Derived Cell Line.Cancer science · 2025Article
- Loss of G-protein coupled receptor 68 in hematopoietic tissues enhances long-term hematopoietic stem cell function upon aging.Stem cell research & therapy · 2025Article
- Integrated cytogenetic and genomic profiling of the MDS-L cell line.Molecular cytogenetics · 2025Article
- Expression levels of genes implicated in the working mechanism of lenalidomide predict treatment response in lower risk myelodysplastic syndrome patients.Haematologica · 2025Article
- The Ubiquitin-Conjugating Enzyme E2 O (UBE2O) and Its Therapeutic Potential in Human Leukemias and Solid Tumors.Cancers · 2024Review
- Review
- LILRB4 regulates multiple myeloma development through STAT3-PFKFB1 pathway.Cell death & disease · 2024Article
- Review
- Article
- Inactivation of p53 provides a competitive advantage to del(5q) myelodysplastic syndrome hematopoietic stem cells during inflammation.Haematologica · 2023Article
- Genome-scale functional genomics identify genes preferentially essential for multiple myeloma cells compared to other neoplasias.Nature cancer · 2023Article
- Calpains, the proteases of two faces controlling the epithelial homeostasis in mammary gland.Frontiers in cell and developmental biology · 2023Review
- G protein-coupled receptor GPR68 inhibits lymphocyte infiltration and contributes to gender-dependent melanoma growth.Frontiers in oncology · 2023Article
- A case of chronic neutrophilic leukemia and multiple myeloma showing the benefits of lenalidomide and cyclophosphamide therapy in treating both conditions.American journal of hematology · 2022Article
- IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia.Nature cancer · 2022Article
- iASPP suppresses Gp78-mediated TMCO1 degradation to maintain CaProceedings of the National Academy of Sciences of the United States of America · 2022Article
- The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia.Leukemia · 2022Article
- Inhibition of host Ogr1 enhances effector CD8Cancer gene therapy · 2021Article
- Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.Cancers · 2021Review
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13 authors at 3 institutions in 2 countries.
Funding
Abstract
Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway.
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