ArticleThe Journal of clinical investigation2013
PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells.
Article in The Journal of clinical investigation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 142 papers.
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Who cites it
142 citing papers in PubMed, 217 citations in OpenAlex.
- H2AX phosphorylation driven by the SET-PP2A axis maintains glioma stem cell properties.Genes & diseases · 2026Article
- Intrinsic cellular resistance to BCR::ABL1 inhibitors.Haematologica · 2026Review
- From fatal disease to functional cure: 25 years of tyrosine kinase inhibition in chronic myeloid leukemia.Leukemia · 2026Review
- Targeting Musashi-2 to counteract senescence and resistance in chronic myeloid leukemia: enhancing the efficacy of imatinib therapy.BMC cancer · 2025Article
- CD133-Guided RNA Nanoparticle Delivery of FTO siRNA Impairs Leukemia Resistance to Tyrosine Kinase Inhibitor Therapy.RNA nanomed · 2025Article
- Review
- CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells.Cell death discovery · 2025Article
- Acquired resistance to molecularly targeted therapies for cancer.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- BCR::ABL1 Proteolysis-targeting chimeras (PROTACs): The new frontier in the treatment of PhLeukemia · 2024Review
- Altering phosphorylation in cancer through PP2A modifiers.Cancer cell international · 2024Review
- Therapeutic Potential of Ceramide in Cancer Treatment.Journal of cancer research and oncobiology · 2024Article
- Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignanciesOncology research · 2024Article
- Article
- Targeting PP2A-dependent autophagy enhances sensitivity to ruxolitinib in JAK2Blood cancer journal · 2023Article
- Article
- Human pancreatic cancer patients with Epithelial-to-Mesenchymal Transition and an aggressive phenotype show a disturbed balance in Protein Phosphatase Type 2A expression and functionality.Journal of translational medicine · 2023Article
- Targeting SAMHD1: To overcome multiple anti-cancer drugs resistance in hematological malignancies.Genes & diseases · 2023Review
- In Silico and In Vivo Studies of a Tumor-Penetrating and Interfering Peptide with Antitumoral Effect on Xenograft Models of Breast Cancer.Pharmaceutics · 2023Article
- Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders.Nature reviews. Drug discovery · 2023Review
- Genomic regulation of transcription and RNA processing by the multitasking Integrator complex.Nature reviews. Molecular cell biology · 2023Review
82 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
45 authors at 14 institutions in 6 countries.
Funding
Abstract
The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression--but not activity--of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/β-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and β-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.
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Registered trials
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.