ArticleProceedings of the National Academy of Sciences of the United States of America2009
A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 90 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
90 citing papers in PubMed, 190 citations in OpenAlex.
- Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q).Annals of hematology · 2021Trial
- Trial
- Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2017Trial
- An exploratory clinical trial of bortezomib in patients with lower risk myelodysplastic syndromes.American journal of hematology · 2017Trial
- Trial
- Trial
- Trial
- Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities.Haematologica · 2011Trial
- Combining lenalidomide with IL-2 family of cytokines enhances activating receptor and perforin/granzyme expression in NK cells.PloS one · 2026Article
- Clinical and Biological Insights into Myelodysplastic Neoplasms Associated with Deletions of Chromosome 5q Region.Hematology reports · 2025Review
- Regulatory mechanisms of PP2A complex assembly driven by physicochemical differences in A-subunit isoforms.Structure (London, England : 1993) · 2025Article
- Advances and challenges in the treatment of myelodysplastic syndromes.Experimental hematology & oncology · 2025Review
- Article
- DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.Leukemia · 2024Article
- Immunodepletion of MDSC by AMV564, a novel bivalent, bispecific CD33/CD3 T cell engager, ex vivo in MDS and melanoma.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- TLR7 ligation augments hematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signaling.Blood advances · 2021Article
- Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.Cancers · 2021Review
- Targeting low-risk myelodysplastic syndrome with novel therapeutic strategies.Trends in molecular medicine · 2021Review
- Review
- Targeting the Microenvironment in MDS: The Final Frontier.Frontiers in pharmacology · 2020Review
30 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
14 authors at 5 institutions in 1 country.
Funding
Abstract
Lenalidomide is the first karyotype-selective therapeutic approved for the treatment of myelodysplastic syndromes (MDS) owing to high rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)]. Although haploinsufficiency for the RPS14 gene and others encoded within the common deleted region (CDR) have been implicated in the pathogenesis of the del(5q) phenotype, the molecular basis of the karyotype specificity of lenalidomide remains unexplained. We focused our analysis on possible haplodeficient enzymatic targets encoded within the CDR that play key roles in cell-cycle regulation. We show that the dual specificity phosphatases, Cdc25C and PP2Acalpha, which are coregulators of the G(2)-M checkpoint, are inhibited by lenalidomide. Gene expression was lower in MDS and acute myeloid leukemia (AML) specimens with del(5q) compared with those with alternate karyotypes. Lenalidomide inhibited phosphatase activity either directly (Cdc25C) or indirectly (PP2A) with corresponding retention of inhibitory phospho-tyrosine residues. Treatment of del(5q) AML cells with lenalidomide induced G(2) arrest and apoptosis, whereas there was no effect in nondel(5q) AML cells. Small interfering RNA (shRNA) suppression of Cdc25C and PP2Acalpha gene expression recapitulated del(5q) susceptibility to lenalidomide with induction of G(2) arrest and apoptosis in both U937 and primary nondel(5q) MDS cells. These data establish a role for allelic haplodeficiency of the lenalidomide inhibitable Cdc25C and PP2Acalpha phosphatases in the selective drug sensitivity of del(5q) MDS.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.