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RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia

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. Intrigui...

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Main Authors: Koschut, David, Ray, Debleena, Li, Zhenhua, Giarin, Emanuela, Groet, Jurgen, Alic, Ivan, Kham, Shirley Kow-Yin, Chng, Wee Joo, Ariffin, Hany Mohd, Weinstock, David M., Yeoh, Allen Eng-Juh, Basso, Giuseppe, Nizetic, Dean
Format: Article
Published: Springer Nature 2021
Subjects:
QD Chemistry
R Medicine
RC Internal medicine
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Online Access:http://eprints.um.edu.my/34530/
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spelling my.um.eprints.345302022-09-15T02:22:07Z http://eprints.um.edu.my/34530/ RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia Koschut, David Ray, Debleena Li, Zhenhua Giarin, Emanuela Groet, Jurgen Alic, Ivan Kham, Shirley Kow-Yin Chng, Wee Joo Ariffin, Hany Mohd Weinstock, David M. Yeoh, Allen Eng-Juh Basso, Giuseppe Nizetic, Dean QD Chemistry R Medicine RC Internal medicine RC0254 Neoplasms. Tumors. Oncology (including Cancer) 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. Springer Nature 2021-01-28 Article PeerReviewed 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 <https://doi.org/10.1038/s41388-020-01567-7>. 10.1038/s41388-020-01567-7
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic QD Chemistry
R Medicine
RC Internal medicine
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
spellingShingle QD Chemistry
R Medicine
RC Internal medicine
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Koschut, David
Ray, Debleena
Li, Zhenhua
Giarin, Emanuela
Groet, Jurgen
Alic, Ivan
Kham, Shirley Kow-Yin
Chng, Wee Joo
Ariffin, Hany Mohd
Weinstock, David M.
Yeoh, Allen Eng-Juh
Basso, Giuseppe
Nizetic, Dean
RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia
description 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.
format Article
author Koschut, David
Ray, Debleena
Li, Zhenhua
Giarin, Emanuela
Groet, Jurgen
Alic, Ivan
Kham, Shirley Kow-Yin
Chng, Wee Joo
Ariffin, Hany Mohd
Weinstock, David M.
Yeoh, Allen Eng-Juh
Basso, Giuseppe
Nizetic, Dean
author_facet Koschut, David
Ray, Debleena
Li, Zhenhua
Giarin, Emanuela
Groet, Jurgen
Alic, Ivan
Kham, Shirley Kow-Yin
Chng, Wee Joo
Ariffin, Hany Mohd
Weinstock, David M.
Yeoh, Allen Eng-Juh
Basso, Giuseppe
Nizetic, Dean
author_sort Koschut, David
title RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia
title_short RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia
title_full RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia
title_fullStr RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia
title_full_unstemmed RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia
title_sort ras-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia
publisher Springer Nature
publishDate 2021
url http://eprints.um.edu.my/34530/
_version_ 1744649185022443520
score 13.211869

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