論文 - 詳細
| RRC ID | 58890 |
|---|---|
| 著者 | Koschut D, Ray D, Li Z, Giarin E, Groet J, Alić I, Kham SK, Chng WJ, Ariffin H, Weinstock DM, Yeoh AE, Basso G, Nižetić D. |
| タイトル | RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia. |
| ジャーナル | Oncogene |
| Abstract |
Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS-ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK-signaling, prevented TSLP-induced RAS-GTP boost. Cytotoxicity assays on primary clinical DS-ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS-inhibitor or PTPN11-inhibitor, but not PI3K/JAK-inhibitors, suggesting a unified treatment target for up to 80% of DS-ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein-activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient-stratification strategy for precision therapy in high-risk ALL. |
| 巻・号 | 40(4) |
| ページ | 746-762 |
| 公開日 | 2021-1-1 |
| DOI | 10.1038/s41388-020-01567-7 |
| PII | 10.1038/s41388-020-01567-7 |
| PMID | 33247204 |
| PMC | PMC7843419 |
| MeSH | Animals Cytokines / physiology Humans Janus Kinase 2 / genetics Janus Kinase 2 / physiology Mice Mutation* Phosphatidylinositol 3-Kinases / physiology Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics* Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology Receptors, Cytokine / genetics Signal Transduction / physiology TOR Serine-Threonine Kinases / physiology ras Proteins / antagonists & inhibitors ras Proteins / genetics ras Proteins / physiology* |
| IF | 7.971 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3(RCB0805) |