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Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq: PQ-2017#305529/2017-0 Deutsche Forschungsgemeinschaft, DFG: MA 1876/12-1 Alexander von Humboldt-Stiftung: 88881.136091/2017-01 RVO-VFN64165, 26/203.214/2017 2018.070.1 Associazione Italiana per la Ricerca sul Cancro, AIRC: IG2015, 17593 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES Cancer Australia: PdCCRS1128727 Cancerfonden Barncancerfonden VetenskapsrÃ¥det, VR Crafoordska Stiftelsen Knut och Alice Wallenbergs Stiftelse Lund University Medical Faculty Foundation Xiamen University, XMU 2014S06 17-74-30019 C7838/A15733 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNSF: 31003A_140913 CNIB Institut National Du Cancer, INCa R01 NCI CA167824 National Institutes of Health, NIH: S10OD018522 2016/2017, 02R/2016 AU 525/1-1 Deutschen Konsortium für Translationale Krebsforschung, DKTK 70112951 Smithsonian Institution, SI Israel Science Foundation, ISF Austrian Science Fund, FWF: W1212 SFB-F06107, SFB-F06105 Acknowledgements BAL received a fellowship provided by CAPES and the Alexander von Humboldt Foundation (#88881.136091/2017-01). ME is supported by CNPq (PQ-2017#305529/2017-0) and FAPERJ-JCNE (#26/203.214/2017) research scholarships, and ZZ by grant RVO-VFN64165. GC is supported by the AIRC Investigator grant IG2015 grant no. 17593 and RS by Cancer Australia grant PdCCRS1128727. This work was supported by grants to RM from the “Georg und Franziska Speyer’sche Hochsschulstiftung”, the “Wilhelm Sander foundation” (grant 2018.070.1) and DFG grant MA 1876/12-1. Acknowledgements This work was supported by The Swedish Childhood Cancer Foundation, The Swedish Cancer Society, The Swedish Research Council, The Knut and Alice Wallenberg Foundation, BioCARE, The Crafoord Foundation, The Per-Eric and Ulla Schyberg Foundation, The Nilsson-Ehle Donations, The Wiberg Foundation, and Governmental Funding of Clinical Research within the National Health Service. Work performed at the Center for Translational Genomics, Lund University has been funded by Medical Faculty Lund University, Region Skåne and Science for Life Laboratory, Sweden. Acknowledgements This work was supported by the Fujian Provincial Natural Science Foundation 2016S016 China and Putian city Natural Science Foundation 2014S06(2), Fujian Province, China. Alexey Ste-panov and Alexander Gabibov were supported by Russian Scientific Foundation project No. 17-74-30019. Jinqi Huang was supported by a doctoral fellowship from Xiamen University, China. Acknowledgments This work was supported by the Swiss National Science Foundation (grant 31003A_140913; OH) and the Cancer Research UK Experimental Cancer Medicine Centre Network, Cardiff ECMCI, grant C7838/A15733. We thank N. Carpino for the Sts-1/2 double-KO mice. Acknowledgements This work was supported by the French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization. We are indebted to all members of our groups for useful discussions and for their critical reading of the manuscript. Special thanks go to Silke Furlan, Friederike Opitz and Bianca Killing. F.A. is supported by the Deutsche For-schungsgemeinschaft (DFG, AU 525/1-1). J.H. has been supported by the German Children’s Cancer Foundation (Translational Oncology Program 70112951), the German Carreras Foundation (DJCLS 02R/2016), Kinderkrebsstiftung (2016/2017) and ERA PerMed GEPARD. Support by Israel Science Foundation, ERA-NET and Science Ministry (SI). A. B. is supported by the German Consortium of Translational Cancer Research, DKTK. We are grateful to the Jülich Supercomputing Centre at the Forschungszemtrum Jülich for granting computing time on the supercomputer JURECA (NIC project ID HKF7) and to the “Zentrum für Informations-und Medientechnologie” (ZIM) at the Heinrich Heine University Düsseldorf for providing computational support to H. G. The study was performed in the framework of COST action CA16223 “LEGEND”. Funding The work was supported by the Austrian Science Fund FWF grant SFB-F06105 to RM and SFB-F06107 to VS and FWF grant W1212 to VS.

Purpose Somatic deletions that affect the lymphoid transcription factor–coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica–Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.

Introduction The ETV6-ABL1 (TEL-ABL) fusion gene is a rare but recurrent genetic aberration found in various hematological malignancies in children and adults. Due to the inverse orientation of ETV6 (12p13) and ABL1 (9q34) an in-frame fusion cannot be produced by a simple balanced translocation and thus results from a complex rearrangement. Alternative splicing generates two fusion transcripts - type A and B without and with ETV6 exon 5, respectively. Both transcripts encode a constitutively active chimeric tyrosine kinase. The effect of ETV6-ABL1 on cellular proliferation, cell survival and transforming capacity mirrors that seen in BCR-ABL1-positive cases. There is a renewed interest in ETV6-ABL1 since the discovery of a "BCR-ABL1-like" (or "Ph-like") gene expression profile (GEP) among B-cell precursor (BCP) ALL cases lacking an established chromosomal abnormality (so-called "B-other ALL"). The BCR-ABL1-like GEP resembles the BCR-ABL1 GEP because both are driven by the activation of kinase signaling. In vitro studies suggest that many of these kinase fusions, including ETV6-ABL1, are sensitive to specific tyrosine kinase inhibitors (TKI), thus representing a promising and relevant therapeutic target, especially given the reported unfavorable prognosis of BCR-ABL1-like ALL. The aim of this study was to characterize the incidence, clinical features and genetic profile of ETV6-ABL1 leukemias with a focus on ALL as an example of a targetable kinase-activating lesion. Patients and methods The cohort totals 44 ETV6-ABL1 patients and comprises newly identified cases (n=9), published cases with additional new data (n=11) and cases with re-examined published data (n=24). Half of the patients (n=22) was diagnosed with ALL (13 children, 9 adults) while 22 had a myeloid malignancy (18 CML-like myeloproliferative neoplasm (MPN), 4 AML). Besides routine diagnostic examinations, we analyzed the presence of fusion transcript variants, genomic profile using MLPA and SNP-array, gene expression profile on microarrays and the presence of BCR-ABL1-like expression signature using quantitative PCR-based low density expression arrays. Results Systematic screening of >3500 cases revealed that ETV6-ABL1 is rare in childhood ALL (0.17% cases) and slightly more prevalent in adult ALL (0.38%). The equal number of MPN and ALL cases and the relative incidence of ALL and MPN in adulthood suggests ETV6-ABL1 is more common in MPN. The type B variant (including ETV6 exon 5) is the dominant transcript and its detection by PCR screening is a more reliable diagnostic approach than FISH with commercial probes for ETV6-RUNX1 and BCR-ABL1. In BCP ALL, ETV6-ABL1 fusion always localized to the der(12) whereas in T-ALL and myeloid cases the fusion localized to the der(9), der(12) or a third chromosome. The genomic profile of ETV6-ABL1 ALL resembled BCR-ABL1 and BCR-ABL1-like ALL with 80% cases having concurrent CDKN2A/B and IKZF1 deletions. The gene expression signature of ETV6-ABL1 ALL cases was more similar to BCR-ABL1 than BCR-ABL1-like principally due to low CRLF2 expression. Nonetheless, 11/12 ETV6-ABL1 ALL cases were classified as BCR-ABL1-like by a standardized qPCR-based expression array. Survival of ETV6-ABL1-positive ALL is 46% in children (6/13 alive) and 13% in adults (1/8 alive). While prognosis of childhood ALL patients responding well to initial treatment seems to be favorable (3/3 with end-induction MRD < 5x10e-5 are in the 1st remission >4 years from diagnosis), children with inferior response have very poor prognosis. Survival of MPN is 50% (9/18 alive) and depends on the disease status at diagnosis (chronic vs. blastic phase). Conclusion ETV6-ABL1 fusion occurs in lymphoid and myeloid leukemia. Its genomic and expression profile, spectrum of malignancies and clinical behavior resemble BCR-ABL1, including the unfavorable prognosis, particularly in acute leukemias. Systematic screening confirmed low frequency of ETV6-ABL1 fusion in ALL. Due to high false-negative rate of FISH, PCR diagnostics are recommended for systematic screening of ALL and FISH-negative CML-like MPN. Despite the generally poor outcome, childhood ALL cases with favorable early treatment response can be treated with standard modern therapeutic protocols. To improve prognosis of the others, early diagnostics of ETV6-ABL1 and treatment with TKI should be considered. Supported by grants IGA MZ NT/13170-4 and GAUK 694414. Disclosures Mullighan: Amgen: Honoraria; Incyte: Consultancy.