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Article: IL10RA Modulates Crizotinib Sensitivity in NPM1-ALK-positive Anaplastic Large Cell Lymphoma

TitleIL10RA Modulates Crizotinib Sensitivity in NPM1-ALK-positive Anaplastic Large Cell Lymphoma
Authors
Keywordscrizotinib
ki-1+ anaplastic large cell lymphoma
npm1 gene
stat3 protein
alk inhibitors
Issue Date2020
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2020, v. 136 n. 14, p. 1657-1669 How to Cite?
AbstractAnaplastic 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 NPM1-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54-90% in clinical trials. However, a subset of patients progress within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide CRISPR activation and knockout screens in ALCL cell lines combined with RNA-seq 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 IL10RA. Elevated IL10RA expression rewires the STAT3 signaling pathway bypassing otherwise critical phosphorylation by NPM1-ALK. IL10RA expression does not correlate with response to standard chemotherapy in pediatric patients suggesting that combination of crizotinib with chemotherapy could prevent ALK-inhibitor resistance-specific relapse. Trials registered as NCT01979536/NCT02034981/UMIN000028075.
Persistent Identifierhttp://hdl.handle.net/10722/283998
ISSN
2020 Impact Factor: 22.113
2020 SCImago Journal Rankings: 5.515
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorProkoph, N-
dc.contributor.authorProbst, NA-
dc.contributor.authorLee, LC-
dc.contributor.authorMonahan, JM-
dc.contributor.authorMatthews, JD-
dc.contributor.authorLiang, HC-
dc.contributor.authorBahnsen, K-
dc.contributor.authorMontes-Mojarro, IA-
dc.contributor.authorAtabay, EK-
dc.contributor.authorSharma, GG-
dc.contributor.authorMalik, Vikas-
dc.contributor.authorLarose, H-
dc.contributor.authorForde, SD-
dc.contributor.authorDucray, SP-
dc.contributor.authorLobello, C-
dc.contributor.authorWang, Q-
dc.contributor.authorLuan, SL-
dc.contributor.authorPospisilova, S-
dc.contributor.authorGambacorti-Passerini, CB-
dc.contributor.authorBurke, A-
dc.contributor.authorPervez, S-
dc.contributor.authorAttarbaschi, A-
dc.contributor.authorJanikova, A-
dc.contributor.authorPacquement, H-
dc.contributor.authorLandman-Parker, J-
dc.contributor.authorLambilliotte, A-
dc.contributor.authorSchleiermacher, G-
dc.contributor.authorKlapper, W-
dc.contributor.authorJauch, R-
dc.contributor.authorWoessmann, W-
dc.contributor.authorVassal, G-
dc.contributor.authorKenner, L-
dc.contributor.authorMerkel, O-
dc.contributor.authorMologni, L-
dc.contributor.authorChiarle, R-
dc.contributor.authorBrugieres, L-
dc.contributor.authorGeoerger, B-
dc.contributor.authorBarbieri, I-
dc.contributor.authorTurner, SD-
dc.date.accessioned2020-07-20T05:55:12Z-
dc.date.available2020-07-20T05:55:12Z-
dc.date.issued2020-
dc.identifier.citationBlood, 2020, v. 136 n. 14, p. 1657-1669-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/283998-
dc.description.abstractAnaplastic 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 NPM1-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54-90% in clinical trials. However, a subset of patients progress within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide CRISPR activation and knockout screens in ALCL cell lines combined with RNA-seq 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 IL10RA. Elevated IL10RA expression rewires the STAT3 signaling pathway bypassing otherwise critical phosphorylation by NPM1-ALK. IL10RA expression does not correlate with response to standard chemotherapy in pediatric patients suggesting that combination of crizotinib with chemotherapy could prevent ALK-inhibitor resistance-specific relapse. Trials registered as NCT01979536/NCT02034981/UMIN000028075.-
dc.languageeng-
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.rightsThis research was originally published in [Journal Title]. Author(s). Title. [Journal Title]. Year;Vol,Issue:pp-pp. © the American Society of Hematology.-
dc.subjectcrizotinib-
dc.subjectki-1+ anaplastic large cell lymphoma-
dc.subjectnpm1 gene-
dc.subjectstat3 protein-
dc.subjectalk inhibitors-
dc.titleIL10RA Modulates Crizotinib Sensitivity in NPM1-ALK-positive Anaplastic Large Cell Lymphoma-
dc.typeArticle-
dc.identifier.emailJauch, R: ralf@hku.hk-
dc.identifier.authorityJauch, R=rp02383-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1182/blood.2019003793-
dc.identifier.pmid32573700-
dc.identifier.scopuseid_2-s2.0-85090428303-
dc.identifier.hkuros310852-
dc.identifier.hkuros318599-
dc.identifier.volume136-
dc.identifier.issue14-
dc.identifier.spage1657-
dc.identifier.epage1669-
dc.identifier.isiWOS:000579872400016-
dc.publisher.placeUnited States-
dc.identifier.issnl0006-4971-

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