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

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Authors

PROKOPH N. PROBST N.A. LEE L.C. MONAHAN J.M. MATTHEWS J.D. LIANG H.C. BAHNSEN K. MONTES-MOJARRO I.A. KARACA-ATABAY E. SHARMA G.G. MALIK V. LAROSE H. FORDE S.D. DUCRAY S.P. LOBELLO Cosimo WANG Q. LUAN S.L. POSPÍŠILOVÁ Šárka GAMBACORTI-PASSERINI C. BURKE G.A.A. PERVEZ S. ATTARBASCHI A. JANIKOVA A. PACQUEMENT H. LANDMAN-PARKER J. LAMBILLIOTTE A. SCHLEIERMACHER G. KLAPPER W. JAUCH R. WOESSMANN W. VASSAL G. KENNER L. MERKEL O. MOLOGNI L. CHIARLE R. BRUGIERES L. GEOERGER B. BARBIERI I. TURNER Suzanne Dawn

Year of publication 2020
Type Article in Periodical
Magazine / Source Blood
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://watermark.silverchair.com/bloodbld2019003793.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA-owggPmBgkqhkiG9w0BBwagggPXMIID0wIBADCCA8wGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMMBbsGzlz9AIOl1NKAgEQgIIDnTVV8rPvZOJ1FU7OOHlmjO32rJ091T_ekg8
Doi http://dx.doi.org/10.1182/blood.2019003793
Keywords NON-HODGKIN-LYMPHOMA; MOLECULAR SIGNATURES; PEDIATRIC-PATIENTS; TYROSINE KINASE; SOLID TUMORS; ALK; EXPRESSION; CHILDREN; ADOLESCENTS; GENE
Description 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.
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