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2 results on '"Bornhauser B"'

1. The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability.

Author

Huang Y, Mouttet B, Warnatz HJ, Risch T, Rietmann F, Frommelt F, Ngo QA, Dobay MP, Marovca B, Jenni S, Tsai YC, Matzk S, Amstislavskiy V, Schrappe M, Stanulla M, Gstaiger M, Bornhauser B, Yaspo ML, and Bourquin JP

Subjects
Basic-Leucine Zipper Transcription Factors genetics, DNA-Binding Proteins genetics, Humans, Translocation, Genetic, E1A-Associated p300 Protein genetics, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Abstract

The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissect its essential transcriptional components and targets by functional genomics. We demonstrate that TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage associated (super-) enhancers to drive lineage identity and self-renewal. Among direct targets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation program crucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferase p300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides a framework for targeting driving transcriptional dependencies in this fatal leukemia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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2. γ-Catenin-Dependent Signals Maintain BCR-ABL1 + B Cell Acute Lymphoblastic Leukemia.

Author

Luong-Gardiol N, Siddiqui I, Pizzitola I, Jeevan-Raj B, Charmoy M, Huang Y, Irmisch A, Curtet S, Angelov GS, Danilo M, Juilland M, Bornhauser B, Thome M, Hantschel O, Chalandon Y, Cazzaniga G, Bourquin JP, Huelsken J, and Held W

Subjects
Animals, Fusion Proteins, bcr-abl genetics, Gene Expression Regulation, Leukemic, Humans, K562 Cells, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Survivin genetics, Survivin metabolism, beta Catenin genetics, beta Catenin metabolism, gamma Catenin genetics, Fusion Proteins, bcr-abl metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Wnt Signaling Pathway, gamma Catenin metabolism
Abstract

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1 + B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. MYC and γ-catenin enabled B-ALL maintenance by augmenting BIRC5 and enforced BIRC5 expression overcame γ-catenin loss. Since γ-catenin was dispensable for normal hematopoiesis, these lineage- and disease-specific features of canonical Wnt signaling identified a potential therapeutic target for the treatment of BCR-ABL1 + B-ALL., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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