| 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
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3(RCB0805) |
