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

Nina Prokoph; Nicola A. Probst; Liam C. Lee; Jack M. Monahan; Jamie D. Matthews; Huan Chang Liang; Klaas Bahnsen; Ivonne A. Montes-Mojarro; Elif Karaca-Atabay; Geeta G. Sharma; Vikas Malik; Hugo Larose; Sorcha D. Forde; Stephen P. Ducray; Cosimo Lobello; Qi Wang; Shi Lu Luan; Šárka Pospíšilová; Carlo Gambacorti-Passerini; G. A.Amos Burke; Shahid Pervez; Andishe Attarbaschi; Andrea Janíková; Hélène Pacquement; Judith Landman-Parker; Anne Lambilliotte; Gudrun Schleiermacher; Wolfram Klapper; Ralf Jauch; Wilhelm Woessmann; Gilles Vassal; Lukas Kenner; Olaf Merkel; Luca Mologni; Roberto Chiarle; Laurence Brugières; Birgit Geoerger; Isaia Barbieri; Suzanne D. Turner

doi:10.1182/blood.2019003793

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

Nina Prokoph, Nicola A. Probst, Liam C. Lee, Jack M. Monahan, Jamie D. Matthews, Huan Chang Liang, Klaas Bahnsen, Ivonne A. Montes-Mojarro, Elif Karaca-Atabay, Geeta G. Sharma, Vikas Malik, Hugo Larose, Sorcha D. Forde, Stephen P. Ducray, Cosimo Lobello, Qi Wang, Shi Lu Luan, Šárka Pospíšilová, Carlo Gambacorti-Passerini, G. A.Amos BurkeShahid Pervez, Andishe Attarbaschi, Andrea Janíková, Hélène Pacquement, Judith Landman-Parker, Anne Lambilliotte, Gudrun Schleiermacher, Wolfram Klapper, Ralf Jauch, Wilhelm Woessmann, Gilles Vassal, Lukas Kenner, Olaf Merkel, Luca Mologni, Roberto Chiarle, Laurence Brugières, Birgit Geoerger, Isaia Barbieri, Suzanne D. Turner^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

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. Key Points: • Genome-wide CRISPR activation and knockout screens identify genes involved in modulating sensitivity to crizotinib in NPM1-ALK⁺ ALCL. • In an autocrine loop, the interleukin-10 receptor activates STAT3, bypassing NPM1-ALK, to bind to the promoters of IL10, IL10RA, and IL10RB.

Original language	English
Pages (from-to)	1657-1669
Number of pages	13
Journal	Blood
Volume	136
Issue number	14
DOIs	https://doi.org/10.1182/blood.2019003793
Publication status	Published - 1 Oct 2020

Bibliographical note

Funding Information:
N.P., H.-C.L., G.G.S., I.A.M.-M., S.P.D., C.L., L.K., O.M., R.C., W.W., C.G.-P., S. Pospisilova, and S.D.T were supported by a European Union Horizon 2020 Marie Skłodowska-Curie Innovative Training Network Grant (675712). L.C.L. was supported by a Cancer Research UK-Cambridge Centre studentship. J.M.M. was supported by the European Molecular Biology Laboratory international program. H.L. was the recipient of a Department of Pathology, University of Cambridge Pathology Centenary Fund studentship. J.D.M. and S.D.F received a PhD studentship from the Alex Hulme Foundation. S. Pospisilova was supported by the Ministry of Health, Czech Republic–Conceptual Development of Research Organization (FNBr, 65269705). R.C. is funded by the National Institutes of Health, National Cancer Institute (5R01-CA196703), I.B. is funded by Cancer Research UK (RG86786), the MAPPYACTS trial by grants from the Institut National du Cancer (PHRC-K14–175), Foundation ARC (grant MAPY201501241) and Association Imagine for Margo, and S.D.T by the Ministry of Education, Youth and Sports of the Czech Republic under project Central European Institute for Technology 2020 (LQ1601).

Funding Information:
The authors thank the National Institutes for Health Research Cambridge Biomedical Research Centre Cell phenotyping hub, the Bauer Core Facility at Harvard University, Elisabeth Gurnhofer, Sandra Högler, Simone Tangermann, Truong Tu Truong, Ricky M. Trigg, Valentina Miano, Luca Pandolfini, Martin Zimmermann, and Tiphaine Adam de Beaumais. N.P. H.-C.L. G.G.S. I.A.M.-M. S.P.D. C.L. L.K. O.M. R.C. W.W. C.G.-P. S. Pospisilova, and S.D.T were supported by a European Union Horizon 2020 Marie Skłodowska-Curie Innovative Training Network Grant (675712). L.C.L. was supported by a Cancer Research UK-Cambridge Centre studentship. J.M.M. was supported by the European Molecular Biology Laboratory international program. H.L. was the recipient of a Department of Pathology, University of Cambridge Pathology Centenary Fund studentship. J.D.M. and S.D.F received a PhD studentship from the Alex Hulme Foundation. S. Pospisilova was supported by the Ministry of Health, Czech Republic–Conceptual Development of Research Organization (FNBr, 65269705). R.C. is funded by the National Institutes of Health, National Cancer Institute (5R01-CA196703), I.B. is funded by Cancer Research UK (RG86786), the MAPPYACTS trial by grants from the Institut National du Cancer (PHRC-K14–175), Foundation ARC (grant MAPY201501241) and Association Imagine for Margo, and S.D.T by the Ministry of Education, Youth and Sports of the Czech Republic under project Central European Institute for Technology 2020 (LQ1601).

Publisher Copyright:
© 2020 American Society of Hematology

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

Access to Document

10.1182/blood.2019003793

Cite this

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, C., Wang, Q., Luan, S. L., Pospíšilová, Š., Gambacorti-Passerini, C., ... Turner, S. D. (2020). IL10RA modulates crizotinib sensitivity in NPM1-ALK⁺ anaplastic large cell lymphoma. Blood, 136(14), 1657-1669. https://doi.org/10.1182/blood.2019003793

@article{34ac313bfea0470a9f2fefbd5b2b22ef,

title = "IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma",

abstract = "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. Key Points: • Genome-wide CRISPR activation and knockout screens identify genes involved in modulating sensitivity to crizotinib in NPM1-ALK+ ALCL. • In an autocrine loop, the interleukin-10 receptor activates STAT3, bypassing NPM1-ALK, to bind to the promoters of IL10, IL10RA, and IL10RB.",

author = "Nina Prokoph and Probst, {Nicola A.} and Lee, {Liam C.} and Monahan, {Jack M.} and Matthews, {Jamie D.} and Liang, {Huan Chang} and Klaas Bahnsen and Montes-Mojarro, {Ivonne A.} and Elif Karaca-Atabay and Sharma, {Geeta G.} and Vikas Malik and Hugo Larose and Forde, {Sorcha D.} and Ducray, {Stephen P.} and Cosimo Lobello and Qi Wang and Luan, {Shi Lu} and {\v S}{\'a}rka Posp{\'i}{\v s}ilov{\'a} and Carlo Gambacorti-Passerini and Burke, {G. A.Amos} and Shahid Pervez and Andishe Attarbaschi and Andrea Jan{\'i}kov{\'a} and H{\'e}l{\`e}ne Pacquement and Judith Landman-Parker and Anne Lambilliotte and Gudrun Schleiermacher and Wolfram Klapper and Ralf Jauch and Wilhelm Woessmann and Gilles Vassal and Lukas Kenner and Olaf Merkel and Luca Mologni and Roberto Chiarle and Laurence Brugi{\`e}res and Birgit Geoerger and Isaia Barbieri and Turner, {Suzanne D.}",

note = "Funding Information: N.P., H.-C.L., G.G.S., I.A.M.-M., S.P.D., C.L., L.K., O.M., R.C., W.W., C.G.-P., S. Pospisilova, and S.D.T were supported by a European Union Horizon 2020 Marie Sk{\l}odowska-Curie Innovative Training Network Grant (675712). L.C.L. was supported by a Cancer Research UK-Cambridge Centre studentship. J.M.M. was supported by the European Molecular Biology Laboratory international program. H.L. was the recipient of a Department of Pathology, University of Cambridge Pathology Centenary Fund studentship. J.D.M. and S.D.F received a PhD studentship from the Alex Hulme Foundation. S. Pospisilova was supported by the Ministry of Health, Czech Republic–Conceptual Development of Research Organization (FNBr, 65269705). R.C. is funded by the National Institutes of Health, National Cancer Institute (5R01-CA196703), I.B. is funded by Cancer Research UK (RG86786), the MAPPYACTS trial by grants from the Institut National du Cancer (PHRC-K14–175), Foundation ARC (grant MAPY201501241) and Association Imagine for Margo, and S.D.T by the Ministry of Education, Youth and Sports of the Czech Republic under project Central European Institute for Technology 2020 (LQ1601). Funding Information: The authors thank the National Institutes for Health Research Cambridge Biomedical Research Centre Cell phenotyping hub, the Bauer Core Facility at Harvard University, Elisabeth Gurnhofer, Sandra H{\"o}gler, Simone Tangermann, Truong Tu Truong, Ricky M. Trigg, Valentina Miano, Luca Pandolfini, Martin Zimmermann, and Tiphaine Adam de Beaumais. N.P. H.-C.L. G.G.S. I.A.M.-M. S.P.D. C.L. L.K. O.M. R.C. W.W. C.G.-P. S. Pospisilova, and S.D.T were supported by a European Union Horizon 2020 Marie Sk{\l}odowska-Curie Innovative Training Network Grant (675712). L.C.L. was supported by a Cancer Research UK-Cambridge Centre studentship. J.M.M. was supported by the European Molecular Biology Laboratory international program. H.L. was the recipient of a Department of Pathology, University of Cambridge Pathology Centenary Fund studentship. J.D.M. and S.D.F received a PhD studentship from the Alex Hulme Foundation. S. Pospisilova was supported by the Ministry of Health, Czech Republic–Conceptual Development of Research Organization (FNBr, 65269705). R.C. is funded by the National Institutes of Health, National Cancer Institute (5R01-CA196703), I.B. is funded by Cancer Research UK (RG86786), the MAPPYACTS trial by grants from the Institut National du Cancer (PHRC-K14–175), Foundation ARC (grant MAPY201501241) and Association Imagine for Margo, and S.D.T by the Ministry of Education, Youth and Sports of the Czech Republic under project Central European Institute for Technology 2020 (LQ1601). Publisher Copyright: {\textcopyright} 2020 American Society of Hematology",

year = "2020",

month = oct,

day = "1",

doi = "10.1182/blood.2019003793",

language = "English",

volume = "136",

pages = "1657--1669",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "14",

}

Prokoph, N, Probst, NA, Lee, LC, Monahan, JM, Matthews, JD, Liang, HC, Bahnsen, K, Montes-Mojarro, IA, Karaca-Atabay, E, Sharma, GG, Malik, V, Larose, H, Forde, SD, Ducray, SP, Lobello, C, Wang, Q, Luan, SL, Pospíšilová, Š, Gambacorti-Passerini, C, Burke, GAA, Pervez, S, Attarbaschi, A, Janíková, 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, Brugières, L, Geoerger, B, Barbieri, I & Turner, SD 2020, 'IL10RA modulates crizotinib sensitivity in NPM1-ALK⁺ anaplastic large cell lymphoma', Blood, vol. 136, no. 14, pp. 1657-1669. https://doi.org/10.1182/blood.2019003793

TY - JOUR

T1 - IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma

AU - Prokoph, Nina

AU - Probst, Nicola A.

AU - Lee, Liam C.

AU - Monahan, Jack M.

AU - Matthews, Jamie D.

AU - Liang, Huan Chang

AU - Bahnsen, Klaas

AU - Montes-Mojarro, Ivonne A.

AU - Karaca-Atabay, Elif

AU - Sharma, Geeta G.

AU - Malik, Vikas

AU - Larose, Hugo

AU - Forde, Sorcha D.

AU - Ducray, Stephen P.

AU - Lobello, Cosimo

AU - Wang, Qi

AU - Luan, Shi Lu

AU - Pospíšilová, Šárka

AU - Gambacorti-Passerini, Carlo

AU - Burke, G. A.Amos

AU - Pervez, Shahid

AU - Attarbaschi, Andishe

AU - Janíková, Andrea

AU - Pacquement, Hélène

AU - Landman-Parker, Judith

AU - Lambilliotte, Anne

AU - Schleiermacher, Gudrun

AU - Klapper, Wolfram

AU - Jauch, Ralf

AU - Woessmann, Wilhelm

AU - Vassal, Gilles

AU - Kenner, Lukas

AU - Merkel, Olaf

AU - Mologni, Luca

AU - Chiarle, Roberto

AU - Brugières, Laurence

AU - Geoerger, Birgit

AU - Barbieri, Isaia

AU - Turner, Suzanne D.

N1 - Funding Information: N.P., H.-C.L., G.G.S., I.A.M.-M., S.P.D., C.L., L.K., O.M., R.C., W.W., C.G.-P., S. Pospisilova, and S.D.T were supported by a European Union Horizon 2020 Marie Skłodowska-Curie Innovative Training Network Grant (675712). L.C.L. was supported by a Cancer Research UK-Cambridge Centre studentship. J.M.M. was supported by the European Molecular Biology Laboratory international program. H.L. was the recipient of a Department of Pathology, University of Cambridge Pathology Centenary Fund studentship. J.D.M. and S.D.F received a PhD studentship from the Alex Hulme Foundation. S. Pospisilova was supported by the Ministry of Health, Czech Republic–Conceptual Development of Research Organization (FNBr, 65269705). R.C. is funded by the National Institutes of Health, National Cancer Institute (5R01-CA196703), I.B. is funded by Cancer Research UK (RG86786), the MAPPYACTS trial by grants from the Institut National du Cancer (PHRC-K14–175), Foundation ARC (grant MAPY201501241) and Association Imagine for Margo, and S.D.T by the Ministry of Education, Youth and Sports of the Czech Republic under project Central European Institute for Technology 2020 (LQ1601). Funding Information: The authors thank the National Institutes for Health Research Cambridge Biomedical Research Centre Cell phenotyping hub, the Bauer Core Facility at Harvard University, Elisabeth Gurnhofer, Sandra Högler, Simone Tangermann, Truong Tu Truong, Ricky M. Trigg, Valentina Miano, Luca Pandolfini, Martin Zimmermann, and Tiphaine Adam de Beaumais. N.P. H.-C.L. G.G.S. I.A.M.-M. S.P.D. C.L. L.K. O.M. R.C. W.W. C.G.-P. S. Pospisilova, and S.D.T were supported by a European Union Horizon 2020 Marie Skłodowska-Curie Innovative Training Network Grant (675712). L.C.L. was supported by a Cancer Research UK-Cambridge Centre studentship. J.M.M. was supported by the European Molecular Biology Laboratory international program. H.L. was the recipient of a Department of Pathology, University of Cambridge Pathology Centenary Fund studentship. J.D.M. and S.D.F received a PhD studentship from the Alex Hulme Foundation. S. Pospisilova was supported by the Ministry of Health, Czech Republic–Conceptual Development of Research Organization (FNBr, 65269705). R.C. is funded by the National Institutes of Health, National Cancer Institute (5R01-CA196703), I.B. is funded by Cancer Research UK (RG86786), the MAPPYACTS trial by grants from the Institut National du Cancer (PHRC-K14–175), Foundation ARC (grant MAPY201501241) and Association Imagine for Margo, and S.D.T by the Ministry of Education, Youth and Sports of the Czech Republic under project Central European Institute for Technology 2020 (LQ1601). Publisher Copyright: © 2020 American Society of Hematology

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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. Key Points: • Genome-wide CRISPR activation and knockout screens identify genes involved in modulating sensitivity to crizotinib in NPM1-ALK+ ALCL. • In an autocrine loop, the interleukin-10 receptor activates STAT3, bypassing NPM1-ALK, to bind to the promoters of IL10, IL10RA, and IL10RB.

AB - 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. Key Points: • Genome-wide CRISPR activation and knockout screens identify genes involved in modulating sensitivity to crizotinib in NPM1-ALK+ ALCL. • In an autocrine loop, the interleukin-10 receptor activates STAT3, bypassing NPM1-ALK, to bind to the promoters of IL10, IL10RA, and IL10RB.

UR - http://www.scopus.com/inward/record.url?scp=85090428303&partnerID=8YFLogxK

U2 - 10.1182/blood.2019003793

DO - 10.1182/blood.2019003793

M3 - Article

C2 - 32573700

AN - SCOPUS:85090428303

SN - 0006-4971

VL - 136

SP - 1657

EP - 1669

JO - Blood

JF - Blood

IS - 14

ER -