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International audience; Recent discoveries of multiple driver mutations open promising perspectives for targeted therapies in meningioma. Nevertheless, iterative recurrences of most aggressive meningiomas as extended skull base meningiomas are not systematically operated and histologically documented. This suggests the interest and the relevance of liquid biopsy in meningiomas. In a proof-of-concept study, we detected the NF2 mutation in 2 of 6 cell-free plasma DNAs and 1 of 1 cerebrospinal fluid (CSF) from high-grade recurrent cases, suggesting that identification of the driver mutation in blood and CSF is today feasible. Liquid biopsy could be an interesting tool to adapt the targeted therapy in meningiomas in the near future.

BACKGROUND Chordomas are malignant bone cancers arising from the skull-base and spine that are rare but cause devastating central nervous system morbidities. Survival is highly variable despite surgery and radiotherapy as 10% live under 1 year and 30-35% survive over 20 years. There are currently no reliable prognostic factors and this limits our ability to tailor patient treatment to their risk. Accordingly, this work identifies epigenetic prognostic chordoma subgroups that are detectable non-invasively through plasma methylomes to guide treatment. METHODS A total of 68 chordoma surgical specimens resected between 1996-2018 across three international centres underwent DNA methylation profiling. Cell-free methylated tumor DNA immunoprecipitation and high-throughput sequencing was performed on available matched plasma samples. RESULTS Two stable tumor clusters were identified through consensus clustering of tissue methylation data. Clusters had statistically significantly different disease-specific survivals (log-rank p=0.0062) independent of clinical factors in a multivariable Cox analysis (HR=16.5, 95%CI: 2.8-96, p=0.0018). The poorer-performing “Immune-infiltrated” cluster had genes hypomethylated at promoters, typically resulting in transcription, within immune-related pathways and higher immune cell abundance within tumors. The better-performing “Cellular” cluster showed higher tumor cellularity plus cell-to-cell interaction and extracellular matrix pathway hypomethylation. Fifty chordoma-versus-other binomial generalized linear models built using plasma methylome data distinguished chordomas from meningiomas and spinal metastases, as representative clinical differential diagnoses, in random left-out 20% testing sets (mean AUROC=0.84, 95%CI: 0.52-1.00). Plasma-based methylation signatures were highly correlated with tissue-based signals within both poor-performing (median r=0.69, 95%CI: 0.66-0.72) and better-performing cluster tumors (median r=0.67, 95%CI: 0.62-0.72). CONCLUSIONS The first identification of two distinct prognostic epigenetic chordoma subgroups is shown here with “Immune-infiltrated” tumors having a poorer prognosis than “Cellular” tumors. Plasma methylomes can be utilized for non-invasive chordoma diagnosis and subtyping. This work may transform chordoma treatment decision-making by guiding surgical planning in advance to match resection aggressiveness with patient prognosis.

Assay of cell-free DNA in blood offers an approach to assessment of tumor DNA. We sought to determine whether Epstein-Barr virus (EBV) DNA in cell-free blood is also a good surrogate for the presence of tumor DNA in children with Hodgkin lymphoma, as it is in adults, and whether it correlates with pediatric outcomes. Pediatric patients enrolled in a Children's Oncology Group trial (AHOD0031) were studied at baseline and at 8 days after the initiation of treatment. At baseline, EBV DNA in cell-free blood correlated with the presence of EBV in tumor, and EBV DNA 8 days after the initiation of therapy predicted inferior event-free survival. EBV DNA in cell-free blood warrants further investigation as a marker of inadequate tumor response in Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Introduction The outcome of very elderly patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) remains poorer than that of younger patients, often because of co-morbidities and physiological organ function impairment. However, the biological specificities of DLBCL in very elderly patients are unknown. The LYSA conducted a multicentric, phase III, open-label, randomized trial in newly diagnosed DLBCL > 80y evaluating the efficacy of the combination of lenalidomide with R-miniCHOP (R2-miniCHOP) in comparison to the standard R-miniCHOP (SENIOR trial, NCT02128061). Based on targeted NGS sequencing and gene expression profile (GEP) analysis, the BIOSENIOR project aimed to provide a molecular characterisation of the cohort and detect clinically relevant biomarkers in according to treatment arm. Methods The SENIOR study enrolled patients aged of 80 years or more with non-previously treated CD20+ DLBCL, age-adjusted IPI= 0 to 3, and Ann Arbor stage II to IV. 249 patients were randomized (127 in R-miniCHOP arm and 122 in R2-miniCHOP arm). Median age was 83y (range 80-96. Patients with available tumor DNA /RNA from FFPE biopsies were included in the BIOSENIOR substudy. GEP was performed using Lymph2CX assay (Nanostring®) and a new RTMLPA assay (Bobée et al. J Mol Diagn 2017) able to quantify the expression of 137 relevant genes involved in B-cell biology, microenvironment or therapeutic response (cereblon). Genotyping (QiaSeq ®) was performed using a dedicated 36 genes panel. GEP features were compared to DLBCL patients < 60y enrolled in the LYSA GAINED trial (NCT01659099). Results Tumor DNA/RNA was available for 164/249 patients (66%). GEP was performed in 154 cases by RTMLPA and in 103 cases by Lymph2CX. The concordance to classify GCB/ABC was of 94% between the two technologies. DLBCL were mainly classified in the ABC subtype [77 = ABC (50%); 53 = GCB (34.4%); 17 unclassified (11%)]. Four cases (2.6%) were classified as EBV+ DLBCL and 1 as PMBL. 81 cases (52.5%) were considered as BCL2+, 23 (15%) as MYC+ and 16 (10.4%) as double-expressors (DE) by GEP. Comparison of GEP with younger patients highlighted distinct features and geriatric specificities (figure 1A). Genotypes were obtained in 159 patients. MYD88, PIM1, CREBBP, CD79B and TP53 were the five most frequently mutated genes (Figure 1B). Correlations between biomarkers and outcomes (OS and PFS) were performed in the overall population and according to treatment arms. The GCB/ABC subtyping, as determined by Lymph2CX (n = 97) was related to OS [HR = 0.38 (0.18 - 0.81) Log-rank: 0.009] and PFS in the overall population. This result was not confirmed in the extended cohort (n = 154) by RTMLPA. The MYC / BCL2 DE status assessed by GEP was a strong predictor of outcome (OS, HR = 2.89 (1.39 - 5.97) Log-rank: 0.003] in both arms. Importantly MYC/BCL2 DE was independent of the IPI score and albuminemia in multivariate analysis. In an exploratory analysis, cereblon (HR = 2.360; CI-95% 1.157-4.812, Log-rank: 0.015) and PD1 [HR = 0.33 (0.16 - 0.66) Log-rank: 0.001] expressions correlate exclusively with PFS in the R2-miniCHOP arm. MYD88 mutations (L265P and others variants) were associated with a worse outcome in the overall population (OS, HR= 2.05, CI-95% 1.190-3.554, Log-rank: 0.008; PFS, HR =1.731, CI-95% 1.059-2.830 Log-rank: 0.027). FOXO1 mutations were detected in 15 patients (9%). Its impact was only observed in the R-miniCHOP arm (OS, HR = 4.07 (1.52 - 10.87) Log-rank: 0.0024; PFS HR = 4.139 (1.59 - 10.79) Log-rank: 0.0016)] and was erased in the R2-miniCHOP arm. TP53 mutations, reported in 24% of cases were predictive of the PFS in the overall population [HR = 1.811 (1.09 - 3.01) Log-rank: 0.0199](prognostic factors are summarized in Table 1). Conclusion BIOSENIOR is an ancillary study of the first prospective phase III trial in ³80 years old patients with newly diagnosed DLBCL. Some biomarkers, known to be predictive in younger patients, are relevant in this cohort, including MYC expression, BCL2/MYC DE, mutations of MYD88, TP53 or FOXO1. However, GEP characteristics of DLBCL occurring in this very old population are highly different of younger patients, suggesting distinct underlying oncogenic mechanisms. BIOSENIOR indicates that, beyond geriatric frailty, molecular features of DLBCL patients > 80y play also a crucial role that should be considered in the design of future trials. Markers that may predict R2-miniCHOP efficacy remain to be confirmed. Disclosures Thieblemont: Janssen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Roche: Honoraria, Research Funding; Cellectis: Membership on an entity's Board of Directors or advisory committees. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Salles:Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Tilly:Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; BMS: Honoraria; Janssen: Honoraria; Gilead: Honoraria; merck: Honoraria; servier: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees. Haioun:celgene: Honoraria; novartis: Honoraria; servier: Honoraria; amgen: Honoraria; janssen cilag: Consultancy; takeda: Consultancy; gilead: Consultancy; celgene: Consultancy; roche: Consultancy. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Casasnovas:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jardin:janssen: Honoraria; roche: Honoraria; amgen: Honoraria; celgene: Honoraria; Servier: Honoraria. OffLabel Disclosure: lenalidomide is evaluatd in combination with RminiHOP

Background Tumour DNA circulates in the plasma of cancer patients admixed with DNA from non-cancerous cells. The genomic landscape of plasma tumour DNA has been characterised in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome in mCRPC has not been extensively explored. Methods mCRPC plasma samples collected from three different centres were concurrently subject to targeted genomic and pan-genome methylation profiling. The treatment courses and outcomes were also obtained. Tumour fraction of each plasma sample was estimated based on heterogyzous SNPs located in two truncal genomic deletions (8q21 and 21q22). Targeted methylome was performed using pre-designed capture panel followed by deep sequencing. We integrated genomic information with methylation data to extract methylation signatures associated with genomically-determined tumour fraction or private to individual's tumour. Results Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically-determined tumour fraction (r=-0.96; P Conclusions Plasma methylome analysis can accurately quantitate tumour fraction and identify distinct biologically-relevant mCRPC phenotypes associated with worse clinical outcome. Clinical trial identification Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy (REC 2192/2013) Royal Marsden, London, UK (REC 04/Q0801/6) PREMIERE trial (EudraCT: 2014-003192-28, NCT02288936). Legal entity responsible for the study The authors. Funding Cancer Research UK (CRUK), Prostate Cancer Foundation (PCF). Disclosure V. Conteduca: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. E. Gonzalez-Billalebeita: Honoraria (self): Astellas; Honoraria (self): Janssen-Cilag; Honoraria (self): Sanofi-Aventis. U.D. Giorgi: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag,; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. G. Attard: Honoraria (self): Institute of Cancer Research; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Arno. All other authors have declared no conflicts of interest.

Background In non-randomized trials, temozolomide (TMZ) has shown activity in about 10% of pts with chemorefractory mCRC bearing MGMT methylation. Methods This multicenter, randomized phase II trial investigated PFS superiority of second-line CAPTEM (Arm A) vs FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts had ECOG PS 0-1, measurable disease, and failed prior oxaliplatin-based therapy. Randomization to arm A (capecitabine 750 mg/sqm b.i.d. days 1-14 plus TMZ 75 mg/sqm b.i.d. days 10-14 q28) or B was stratified according to time elapsed from the start of oxaliplatin-based therapy and PD ( Results A total of 86 pts were randomized (43 per arm). After a median follow-up of 30.5 months (IQR 12.2-36.3), 79 disease PFS events occurred. PFS and OS were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) months in arm A vs 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B (HR = 1.86 [0.82-1.72] and HR = 0.97 [0.58-1.61]), respectively. ORR and DCR were 11.6% and 53.5% in both arms. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. In the subgroup with negative MGMT IHC expression, there were no significant differences between the two arms in terms of activity and efficacy endpoints, whereas in pts with positive MGMT IHC expression CAPTEM regimen was associated with significantly inferior outcomes in terms of PFS (2.0 vs 3.5 mos; HR = 2.08 [1.02-4.21]), OS (5.7 vs 10.6 mos; OR = 1.07 [0.39-2.93]) and DCR (15.4 vs 56.5%; OR = 0.23 [0.04-0.99]), interaction test p = 0.125, 0.732, 0.028. Predicting outcomes with MB was more accurate when using ctDNA vs tumor DNA. Conclusions TMZ-based treatment should be investigated by a phase III trial, ideally conducted in patients with MGMT methylated/MGMT IHC negative tumors. Clinical trial identification NCT02414009. Legal entity responsible for the study Fondazione IRCCS Istituto Nazionale Tumori di Milano. Funding Fondazione IRCCS Istituto Nazionale Tumori di Milano. Disclosure F. Pietrantonio: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier. F. Morano: Honoraria (self): Servier Italia SpA . S. Lonardi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Bristol-Mayers-Squibb. L. Rimassa: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Sirtex Medical; Honoraria (self), Advisory / Consultancy: Italfarmaco; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Baxter; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: ArQule; Honoraria (self), Advisory / Consultancy: Xelixis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Eisai. A. Sartore-Bianchi: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Honoraria (self), Advisory / Consultancy: TizianaLife Sciences; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Pharm Research Associated; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Octimet Oncology; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Teofarma; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Gentili; Speaker Bureau / Expert testimony: Fondazione Menarini. All other authors have declared no conflicts of interest.

The fields of cell biology and cancer research are deeply saddened by the untimely death of Alan Hall at the young age of 62. There will be many obituaries, so in this remembrance I would like to describe some events in Alan’s career, and give a personal view on what I think made him an

Introduction: B-cell malignancies may depend on the histone methyltransferase EZH2 to perpetuate a less differentiated state, with activating mutations of EZH2 being potential oncogenic drivers. Tazemetostat, a potent, selective EZH2 inhibitor, is in phase 2 clinical development in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). Objective responses were observed in patients (pts) with EZH2 mutant or wild type tumors in the phase 1 part of the phase 1/2 study. The ongoing phase 2 study is enrolling pts with mutant or wild type EZH2 having R/R diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) to determine efficacy and safety. The primary endpoint is overall response rate. Here we report results of an updated molecular analysis of archived tumor and circulating tumor DNA (ctDNA) collected from pts plasma and associations with preliminary response data, including the discovery of novel candidate molecular predictors of tazemetostat response. Methods: Archived tumor and/or plasma-derived ctDNA samples were obtained during screening from R/R DLBCL and FL pts enrolled to the phase 2 trial of tazemetostat in NHL (NCT01897571). Next generation sequencing was performed retrospectively on archived tumor DNA (target coverage of 1,500X) and ctDNA (20,000X for somatic mutations and 5,000X for structural alterations). DNA was isolated from archived tumor and was tested across a panel of approximately 200 genes, including 62 genes commonly altered in NHL to identify somatic mutations, amplifications, and translocations. The ctDNA sequencing was restricted to the 62 gene NHL panel. Best objective overall response data (Cheson 2007) as of May 1, 2018 were used to generate two groups: responders (R = CR + PR), and non-responders (NR = progressive disease, stable disease, or unknown clinical response). Fisher's exact test (two tailed) was performed to identify DNA variants associated with either the R or NR groups for FL+DLBCL combined and for each NHL sub-type independently (Table 1). All gene associations met an unadjusted P-value threshold of ≤ 0.1. Results: In the combined analysis for all NHL pts, EZH2, BRCA2, ETV6, IKZF3 and TNFRSF14 mutations were associated with clinical response. Eleven genes, including BCL6, BCL2, TP53, PIM1, HIST1H1B and HIST1H1E, mutations were associated with a lack of response to tazemetostat. Association of detection of mutations in EZH2, BCL6 and HIST1H1E and response were detected in both ctDNA and archived tumor analysis, with all other genes achieving P ≤ 0.1 in either the ctDNA or the archived tumor analysis. Analysis of the NHL subcategories revealed in FL that mutations in EZH2 and STAT6 were associated with clinical response while mutations in BCL2, TNFAIP3, FOXO1 and MYD88 were identified as negative predictors. EZH2 was the only gene identified in both the ctDNA and archived tumor analyses in FL. In DLBCL, while EZH2 was not detected as a predictor of response to tazemetostat at P ≤ 0.1, the number of pts with mutant rather than wild type EZH2 was higher in responders than non-responders in both analyses. Positive predictors of tazemetostat response were detected in DLBCL: MYD88, MEF2B, ETV6, MLH1, RECQL4, and RNF43. Negative predictors of response were also identified in DLBCL: BCL2, PDL1, PDL2 and SOCS1. When the genes identified as associated with tazemetostat response in DLBCL were compared between the archived tumor and ctDNA analyses, no genes in common were identified. Conclusions: These analyses confirm genes previously described as potential predictors of tazemetostat response in analyses using smaller patient numbers and less mature clinical response data such as STAT6, EZH2, MYD88, TP53,BCL2, BCL6, PIM1 and HIST1H1E. In addition, identification of PDL1/PDL2 and RECQL4/MLH1/BRCA2 as novel predictors points to potential relevance of immune checkpoint and DNA damage repair pathways as additional pathways that may be of relevance to tazemetostat response in NHL. Subanalyses performed independently on each NHL subtype revealed disease specific biomarkers of response that may point to differences in the factors that can influence response to tazemetostat in DLBCL and FL. Disclosures McDonald: Epizyme: Employment, Equity Ownership. Thomas:Epizyme: Employment, Equity Ownership. Daigle:Epizyme: Employment, Equity Ownership. Morschhauser:Epizyme: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Salles:Morphosys: Honoraria; Servier: Honoraria; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria; Pfizer: Honoraria; Servier: Honoraria, Other: Advisory Board; Merck: Honoraria; BMS: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Amgen: Honoraria; Epizyme: Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Ribrag:Servier, Pharmamar, Nanostring, Gilead, Infinity, BMS, MSD, Epizyme: Consultancy; ESAI: Honoraria, Research Funding; Roche: Other: Travel, expenses, accommodation. McKay:Epizyme: Consultancy, Honoraria. Tilly:Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Johnson:Kite: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Bristol-Myers Squibb: Honoraria; Eisai: Research Funding; Takeda: Honoraria, Travel, accommodations, expenses; Boeringher Ingelheim: Consultancy; Epizyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Dickinson:GSK: Consultancy. Opat:Roche, Celgene, Mundipharma, Janssen: Honoraria; Roche, Celgene, Mundipharma, Janssen: Consultancy. Jurczak:Gilead: Consultancy; Morphosys: Research Funding; Roche: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; European Medicines Agency: Consultancy; AstraZeneca/Acerta: Consultancy, Research Funding; Sandoz-Nowartis: Consultancy; Afimed: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Nordic Nanovector: Research Funding; Janssen: Consultancy. Cartron:Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Roche: Consultancy, Honoraria. Zinzani:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Astra Zeneca: Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Assouline:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau. Radford:BMS: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Celgene: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; ADC Therapeutics: Consultancy, Research Funding. Gribben:Novartis: Honoraria; Medical Research Council: Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Cancer Research UK: Research Funding; Kite: Honoraria; NIH: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Honoraria; Unum: Equity Ownership; Wellcome Trust: Research Funding. Haioun:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Le Gouill:Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria. Clawson:Epizyme: Employment, Equity Ownership. Larus:Epizyme: Employment, Equity Ownership. Blakemore:Epizyme: Employment, Equity Ownership.

Site-specific deletions in the tal-1 gene are reported to occur in 12-26% of T cell acute lymphoblastic leukemias (T-ALL). So far two main types of tal-1 deletions have been described. Upon analysis of 134 T-ALL we have found two new types of tal-1 deletions. These four types of deletions juxtapose the 5' part of the tal-1 gene to the sil gene promoter, thereby deleting all coding sil exons but leaving the coding tal-1 exons undamaged. The recombination signal sequences (RSS) and fusion regions of the tal-1 deletion breakpoints strongly resemble the RSS and junctional regions of immunoglobulin/T cell receptor (TCR) gene rearrangements, which implies that they are probably caused by the same V(D)J recombinase complex. Analysis of the 134 T-ALL suggested that the occurrence of tal-1 deletions is associated with the CD3 phenotype, because no tal-1 deletions were found in 25 TCR-gamma/delta + T-ALL, whereas 8 of the 69 CD3- T-ALL and 11 of the 40 TCR-alpha/beta + T-ALL contained such a deletion. Careful examination of all TCR genes revealed that tal-1 deletions exclusively occurred in CD3- or CD3+ T-ALL of the alpha/beta lineage with a frequency of 18% in T-ALL with one deleted TCR-delta allele, and a frequency of 34% in T-ALL with TCR-delta gene deletions on both alleles. Therefore, we conclude that alpha/beta lineage commitment of the T-ALL and especially the extent of TCR-delta gene deletions determines the chance of a tal-1 deletion. This suggests that tal-1 deletions are mediated via the same deletion mechanism as TCR-delta gene deletions.