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Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

ABSTRACT: TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.

SUBMITTER: Fischer U

PROVIDER: S-EPMC4603357 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

Fischer Ute U Forster Michael M Rinaldi Anna A Risch Thomas T Sungalee Stéphanie S Warnatz Hans-Jörg HJ Bornhauser Beat B Gombert Michael M Kratsch Christina C Stütz Adrian M AM Sultan Marc M Tchinda Joelle J Worth Catherine L CL Amstislavskiy Vyacheslav V Badarinarayan Nandini N Baruchel André A Bartram Thies T Basso Giuseppe G Canpolat Cengiz C Cario Gunnar G Cavé Hélène H Dakaj Dardane D Delorenzi Mauro M Dobay Maria Pamela MP Eckert Cornelia C Ellinghaus Eva E Eugster Sabrina S Frismantas Viktoras V Ginzel Sebastian S Haas Oskar A OA Heidenreich Olaf O Hemmrich-Stanisak Georg G Hezaveh Kebria K Höll Jessica I JI Hornhardt Sabine S Husemann Peter P Kachroo Priyadarshini P Kratz Christian P CP Te Kronnie Geertruy G Te Kronnie Geertruy G Marovca Blerim B Niggli Felix F McHardy Alice C AC Moorman Anthony V AV Panzer-Grümayer Renate R Petersen Britt S BS Raeder Benjamin B Ralser Meryem M Rosenstiel Philip P Schäfer Daniel D Schrappe Martin M Schreiber Stefan S Schütte Moritz M Stade Björn B Thiele Ralf R von der Weid Nicolas N Vora Ajay A Zaliova Marketa M Zhang Langhui L Zichner Thomas T Zimmermann Martin M Lehrach Hans H Borkhardt Arndt A Bourquin Jean-Pierre JP Franke Andre A Korbel Jan O JO Stanulla Martin M Yaspo Marie-Laure ML

Nature genetics 20150727 9

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperati ...[more]

PMID: 26214592

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Project description:Background B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent pediatric cancer worldwide. Despite improvements in treatment regimens, approximately 20% of the cases cannot be cured, highlighting the necessity for identifying new biomarkers to improve the current clinical and molecular risk stratification schemes. We aimed to investigate whether LINC00173 is a biomarker in ALL and to explore its expression level in other human cancer types. Methods A nested case–control study including Mexican children with BCP-ALL was conducted. LINC00173 expression was evaluated by qRT-PCR using hydrolysis probes. To validate our findings, RNA-seq expression data from BCP-ALL and normal tissues were retrieved from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) repositories, respectively. LINC00173 expression was also evaluated in solid tumors by downloading available data from The Cancer Genome Atlas (TCGA). Results A lower expression of LINC00173 in BCP-ALL cases compared to normal subjects was observed (p < 0.05). ALL patients who carry the TCF3/PBX1 fusion gene displayed lower expression of LINC00173 in contrast to other BCP-ALL molecular subtypes (p < 0.04). LINC00173 underexpression was associated with a high risk to relapse (HR = 1.946, 95% CI = 1.213–3.120) and die (HR = 2.073, 95% CI = 1.211–3.547). Patients with TCF3/PBX1 and underexpression of LINC00173 had the worst prognosis (DFS: HR = 12.24, 95% CI = 5.04–29.71; OS: HR = 11.19, 95% CI = 26–32). TCGA data analysis revealed that underexpression of LINC00173 is also associated with poor clinical outcomes in six new reported tumor types. Conclusion Our findings suggest that LINC00173 is a biomarker of poor prognosis in BCP-ALL and other types of cancer. We observed an association between the expression of LINC00173 and TCF3/PBX1 and the risk to relapse and die in BCP-ALL, which is worse in TCF3/PBX1-positive cases displaying underexpression of LINC00173. Experimental studies are needed to provide insight into the LINC00173 and TCF3/PBX relationship.

Dataset Information

Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

Publications

Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

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