IL10RA modulates crizotinib sensitivity in NPM1-ALK(+) anaplastic large cell lymphoma

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F20%3A00118318" target="_blank" >RIV/00216224:14740/20:00118318 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/65269705:_____/20:00073376

Výsledek na webu

<a href="https://watermark.silverchair.com/bloodbld2019003793.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA-owggPmBgkqhkiG9w0BBwagggPXMIID0wIBADCCA8wGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMMBbsGzlz9AIOl1NKAgEQgIIDnTVV8rPvZOJ1FU7OOHlmjO32rJ091T_ekg8" target="_blank" >https://watermark.silverchair.com/bloodbld2019003793.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA-owggPmBgkqhkiG9w0BBwagggPXMIID0wIBADCCA8wGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMMBbsGzlz9AIOl1NKAgEQgIIDnTVV8rPvZOJ1FU7OOHlmjO32rJ091T_ekg8</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/blood.2019003793" target="_blank" >10.1182/blood.2019003793</a>

Jazyk výsledku

angličtina

Název v původním jazyce

IL10RA modulates crizotinib sensitivity in NPM1-ALK(+) anaplastic large cell lymphoma

Popis výsledku v původním jazyce

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

Název v anglickém jazyce

IL10RA modulates crizotinib sensitivity in NPM1-ALK(+) anaplastic large cell lymphoma

Popis výsledku anglicky

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

<a href="/cs/project/LQ1601" target="_blank" >LQ1601: CEITEC 2020</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Blood

ISSN

0006-4971

e-ISSN

—

Svazek periodika

136

Číslo periodika v rámci svazku

14

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

1657-1669

Kód UT WoS článku

000579872400016

EID výsledku v databázi Scopus

2-s2.0-85090428303