Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.

ADC Therapeutics Limited London UK

Center for Biomarker Research in Medicine Core Lab 2 Medical University of Vienna Vienna Austria

Central European Institute of Technology Masaryk University Brno Czech Republic

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Department of Biochemistry University of Washington Seattle WA USA

Department of Computational Biology St Jude Children's Research Hospital Memphis TN USA

Department of Dermatology HELIOS Hospital Krefeld Krefeld Department of Dermatology and Allergy Charité Universitätsmedizin Berlin Berlin Germany

Department of Dermatology Medical University of Graz Graz Austria

Department of Hematology Oncology and Cancer Immunology Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany and Experimental and Clinical Research Center a joint cooperation between the MDC and Charité Berlin Germany

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of Pathology and Laboratory Medicine Aga Khan University Hospital Karachi Pakistan

Department of Pathology Hematopathology Section University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Pathology Henri Mondor University Hospital AP HP INSERM U955 University Paris East Créteil France

Department of Pathology Unit of Experimental and Laboratory Animal Pathology Medical University of Vienna Vienna Austria

Department of Pediatric Oncology Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Pharmacology Physiology and Microbiology Division Pharmacology Karl Landsteiner University of Health Sciences Krems Austria

Departments of Molecular and Cellular Physiology and Structural Biology Stanford University School of Medicine Stanford CA USA

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Addenbrooke's Hospital Cambridge UK

Division of Haematopathology European Institute of Oncology IRCCS Milan Italy

Division of Life Science The Hong Kong University of Science and Technology Kowloon Hong Kong

European Research Initiative on ALK Related Malignancies Suzanne Turner Cambridge UK

German Cancer Consortium Heidelberg Germany

Group Biology of Malignant Lymphomas Max Delbrück Center for Molecular Medicine Berlin Germany

Hematology Department Necker University Hospital Assistance Publique Hôpitaux de Paris and Institut Necker Enfants Malades INSERM UMR1151 Université de Paris Paris France

Howard Hughes Medical Institute Chevy Chase MD USA

Institute for Protein Design University of Washington Seattle WA USA

Institute of Pathology and Neuropathology University Hospital and Comprehensive Cancer Center Tübingen Tübingen Germany

Institute of Pathology Lausanne University Hospital and Lausanne University Lausanne Switzerland

Institute of Pathology University of Würzburg Würzburg Germany

Pediatric Hematology and Oncology University Hospital Hamburg Eppendorf Hamburg Germany

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

Zobrazit více v PubMed

Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat. Rev. Cancer. 2008;8:11–23. doi: 10.1038/nrc2291. PubMed DOI

Swerdlow SH, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–2390. doi: 10.1182/blood-2016-01-643569. PubMed DOI PMC

Brown RA, Fernandez-Pol S, Kim J. Primary cutaneous anaplastic large cell lymphoma. J. Cutan. Pathol. 2017;44:570–577. doi: 10.1111/cup.12937. PubMed DOI

Horwitz S, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393:229–240. doi: 10.1016/S0140-6736(18)32984-2. PubMed DOI PMC

Mussolin, L. et al. Prognostic factors in childhood anaplastic large cell lymphoma: long term results of the international ALCL99 trial. Cancers12, 2747 (2020). PubMed PMC

Knorr F, et al. Stem cell transplantation and vinblastine monotherapy for relapsed pediatric anaplastic large cell lymphoma: results of the international, prospective ALCL-relapse trial. J. Clin. Oncol. 2020;38:3999–4009. doi: 10.1200/JCO.20.00157. PubMed DOI

Parrilla Castellar ER, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124:1473–1480. doi: 10.1182/blood-2014-04-571091. PubMed DOI PMC

Laimer D, et al. PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas. Nat. Med. 2012;18:1699–1704. doi: 10.1038/nm.2966. PubMed DOI

Mathas S, et al. Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma. Proc. Natl Acad. Sci. USA. 2009;106:5831–5836. doi: 10.1073/pnas.0900912106. PubMed DOI PMC

Mathas S, et al. Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa B. EMBO J. 2002;21:4104–4113. doi: 10.1093/emboj/cdf389. PubMed DOI PMC

Agnelli L, et al. Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma. Blood. 2012;120:1274–1281. doi: 10.1182/blood-2012-01-405555. PubMed DOI

Schleussner, N. et al. The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma. Leukemia32, 1994–2007 (2018). PubMed PMC

Matsuyama H, et al. miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma. Blood. 2011;118:6881–6892. doi: 10.1182/blood-2011-05-354654. PubMed DOI

Malcolm TI, et al. Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress. Nat. Commun. 2016;7:10087. doi: 10.1038/ncomms10087. PubMed DOI PMC

Ambrogio C, et al. NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells. Cancer Res. 2009;69:8611–8619. doi: 10.1158/0008-5472.CAN-09-2655. PubMed DOI PMC

Bonzheim I, et al. Anaplastic large cell lymphomas lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling. Blood. 2004;104:3358–3360. doi: 10.1182/blood-2004-03-1037. PubMed DOI

Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity. 2010;33:153–165. doi: 10.1016/j.immuni.2010.08.004. PubMed DOI PMC

Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol. Res. 2015;3:219–227. doi: 10.1158/2326-6066.CIR-15-0009. PubMed DOI PMC

Janik JE, et al. Elevated serum-soluble interleukin-2 receptor levels in patients with anaplastic large cell lymphoma. Blood. 2004;104:3355–3357. doi: 10.1182/blood-2003-11-3922. PubMed DOI

Zhang Q, et al. IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK. Proc. Natl Acad. Sci. USA. 2011;108:11977–11982. doi: 10.1073/pnas.1100319108. PubMed DOI PMC

Hnisz D, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155:934–947. doi: 10.1016/j.cell.2013.09.053. PubMed DOI PMC

Loven J, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153:320–334. doi: 10.1016/j.cell.2013.03.036. PubMed DOI PMC

Gryder BE, et al. PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov. 2017;7:884–899. doi: 10.1158/2159-8290.CD-16-1297. PubMed DOI PMC

Whyte WA, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153:307–319. doi: 10.1016/j.cell.2013.03.035. PubMed DOI PMC

Chiarle R, et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat. Med. 2005;11:623–629. doi: 10.1038/nm1249. PubMed DOI

Weilemann A, et al. Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma. Blood. 2015;125:124–132. doi: 10.1182/blood-2014-08-594507. PubMed DOI

Lollies A, et al. An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma. Leukemia. 2018;32:92–101. doi: 10.1038/leu.2017.203. PubMed DOI

Prutsch N, et al. Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma. Leukemia. 2019;33:696–709. doi: 10.1038/s41375-018-0239-1. PubMed DOI PMC

Crescenzo R, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27:516–532. doi: 10.1016/j.ccell.2015.03.006. PubMed DOI PMC

Iqbal J, et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood. 2010;115:1026–1036. doi: 10.1182/blood-2009-06-227579. PubMed DOI PMC

Lechner MG, et al. Breast implant-associated, ALK-negative, T-cell, anaplastic, large-cell lymphoma: establishment and characterization of a model cell line (TLBR-1) for this newly emerging clinical entity. Cancer. 2011;117:1478–1489. doi: 10.1002/cncr.25654. PubMed DOI PMC

Watanabe M, et al. JunB induced by constitutive CD30-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling activates the CD30 promoter in anaplastic large cell lymphoma and reed-sternberg cells of Hodgkin lymphoma. Cancer Res. 2005;65:7628–7634. doi: 10.1158/0008-5472.CAN-05-0925. PubMed DOI

Watanabe M, et al. AP-1 mediated relief of repressive activity of the CD30 promoter microsatellite in Hodgkin and Reed-Sternberg cells. Am. J. Pathol. 2003;163:633–641. doi: 10.1016/S0002-9440(10)63690-5. PubMed DOI PMC

Pedersen MB, et al. High intratumoral macrophage content is an adverse prognostic feature in anaplastic large cell lymphoma. Histopathology. 2014;65:490–500. doi: 10.1111/his.12407. PubMed DOI

Knorr F, et al. Blood cytokine concentrations in pediatric patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Haematologica. 2018;103:477–485. doi: 10.3324/haematol.2017.177972. PubMed DOI PMC

Silva DA, et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature. 2019;565:186–191. doi: 10.1038/s41586-018-0830-7. PubMed DOI PMC

Lamant L, et al. Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J. Clin. Oncol. 2011;29:4669–4676. doi: 10.1200/JCO.2011.36.5411. PubMed DOI

Seidemann K, et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM 90. Blood. 2001;97:3699–3706. doi: 10.1182/blood.V97.12.3699. PubMed DOI

Flynn MJ, et al. ADCT-301, a pyrrolobenzodiazepine (PBD) dimer-containing antibody-drug conjugate (ADC) targeting CD25-expressing hematological malignancies. Mol. Cancer Therapeutics. 2016;15:2709–2721. doi: 10.1158/1535-7163.MCT-16-0233. PubMed DOI

Janik JE, et al. 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma. Proc. Natl Acad. Sci. USA. 2015;112:13045–13050. doi: 10.1073/pnas.1516107112. PubMed DOI PMC

Mathas S, et al. Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa B. EMBO J. 2002;21:4104–4113. doi: 10.1093/emboj/cdf389. PubMed DOI PMC

Ghandi M, et al. Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019;569:503–508. doi: 10.1038/s41586-019-1186-3. PubMed DOI PMC

Feldman AL, et al. Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas. Leukemia. 2009;23:574–580. doi: 10.1038/leu.2008.320. PubMed DOI PMC

Chen J, et al. Cytokine receptor signaling is required for the survival of ALK- anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations. Proc. Natl Acad. Sci. USA. 2017;114:3975–3980. doi: 10.1073/pnas.1700682114. PubMed DOI PMC

de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J. Immunol. 1993;150:4754–4765. PubMed

Vasmatzis G, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood. 2012;120:2280–2289. doi: 10.1182/blood-2012-03-419937. PubMed DOI PMC

Hapgood G, et al. Identification of high-risk DUSP22-rearranged ALK-negative anaplastic large cell lymphoma. Br. J. Haematol. 2019;186:e28–e31. PubMed PMC

Fauconneau A, et al. Assessment of diagnostic criteria between primary cutaneous anaplastic large-cell lymphoma and CD30-rich transformed mycosis fungoides; a study of 66 cases. Br. J. Dermatol. 2015;172:1547–1554. doi: 10.1111/bjd.13690. PubMed DOI

d’Amore F, et al. Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2015;26:v108–v115. doi: 10.1093/annonc/mdv201. PubMed DOI

Mosse YP, et al. Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: A Children’s Oncology Group Study. J. Clin. Oncol. 2017;35:3215–3221. doi: 10.1200/JCO.2017.73.4830. PubMed DOI PMC

Sharma, G. G. et al. Tumor resistance against ALK targeted therapy-where it comes from and where it goes. Cancers10, 62 (2018). PubMed PMC

Wang TT, et al. IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective gamma-chain cytokines, decreases leukemic T-cell viability. Leukemia. 2019;33:1243–1255. doi: 10.1038/s41375-018-0290-y. PubMed DOI PMC

Prince HM, et al. Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J. Clin. Oncol. 2010;28:1870–1877. doi: 10.1200/JCO.2009.26.2386. PubMed DOI

Kung Sutherland MS, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 2013;122:1455–1463. doi: 10.1182/blood-2013-03-491506. PubMed DOI

Zammarchi, F. et al. CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity. J Immunother Cancer8, e000860 (2020). PubMed PMC

Puzanov I, et al. First-in-human study of camidanlumab tesirine (ADCT-301, Cami), an anti-CD25 targeted therapy in patients (pts) with advanced solid tumours: Pharmacokinetics (PK) and biomarker evaluation. Ann. Oncol. 2020;31:S710–S711. doi: 10.1016/j.annonc.2020.08.1150. DOI

Boni, J. et al. Pharmacokinetic and pharmacodynamic correlates from the phase 1 study of camidanlumab tesirine (Cami) in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma. Blood136, 35–36 (2020).

Mansour MR, et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science. 2014;346:1373–1377. doi: 10.1126/science.1259037. PubMed DOI PMC

Sanda T, et al. TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia. Cancer Discov. 2013;3:564–577. doi: 10.1158/2159-8290.CD-12-0504. PubMed DOI PMC

Kozlova V, et al. CD20 is dispensable for B-cell receptor signaling but is required for proper actin polymerization, adhesion and migration of malignant B cells. PloS ONE. 2020;15:e0229170. doi: 10.1371/journal.pone.0229170. PubMed DOI PMC

Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods. 2014;11:783–784. doi: 10.1038/nmeth.3047. PubMed DOI PMC

STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms