Koschut, David and Ray, Debleena and Li, Zhenhua and Giarin, Emanuela and Groet, Jurgen and Alic, Ivan and Kham, Shirley Kow-Yin and Chng, Wee Joo and Ariffin, Hany Mohd and Weinstock, David M. and Yeoh, Allen Eng-Juh and Basso, Giuseppe and Nizetic, Dean (2021) RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia. Oncogene, 40 (4). pp. 746-762. ISSN 0950-9232, DOI https://doi.org/10.1038/s41388-020-01567-7.
Full text not available from this repository.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 DSALL 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.
| Item Type: | Article |
|---|---|
| Funders: | Singapore Ministry of Education Academic Research Funds Tier 2 grants[2015-T2-2-119], Singapore Ministry of Education Academic Research Funds Tier 2 grants[2015-T2-1-023], Fondazione AIRC per la ricerca sul cancro[IG 19186], Fondazione Cariparo[17/07] |
| Uncontrolled Keywords: | Leukemias;Down syndrome;Inhibitors;Mutation status;Therapy |
| Subjects: | Q Science > QD Chemistry R Medicine R Medicine > RC Internal medicine R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 15 Sep 2022 02:22 |
| Last Modified: | 15 Sep 2022 02:22 |
| URI: | http://eprints.um.edu.my/id/eprint/34530 |
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