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.
Subject(s)
E1A-Associated p300 Protein/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Basic-Leucine Zipper Transcription Factors/genetics , DNA-Binding Proteins/genetics , Humans , Translocation, GeneticSubject(s)
Antibodies, Bispecific/drug effects , Antineoplastic Agents, Immunological/therapeutic use , Hematopoietic Stem Cell Transplantation , Oncogene Proteins, Fusion/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/adverse effects , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Combined Modality Therapy , Consolidation Chemotherapy , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Transplantation, Homologous , Treatment OutcomeABSTRACT
OBJECTIVES: This study aimed to: (i) analyse the antibiotic susceptibility testing (AST) profiles of extended spectrum ß-lactamase (ESBL)- and AmpC ß-lactamase-producing clinical Enterobacteriaceae isolates applying EUCAST 2013 AST guidelines; and (ii) evaluate discrepancies in AST profiles according to EUCAST 2010 guidelines, EUCAST 2013 guidelines, CLSI 2009 guidelines and CLSI 2013 guidelines. METHODS: The 195 ESBL- and/or AmpC ß-lactamase-producing Enterobacteriaceae isolates used in this study were systematically characterized by disc diffusion AST interpreted according to the 2013 guidelines of EUCAST and CLSI, the EUCAST 2010 guidelines and the CLSI 2009 guidelines. RESULTS: Individual cephalosporin AST patterns according to EUCAST 2013 guidelines were described for individual ESBL and AmpC ß-lactamase genotypes. Significant differences in the susceptibility rates of important cephalosporins such as cefepime, ceftazidime and cefotaxime applying EUCAST 2013 and CLSI 2013 AST guidelines were demonstrated for ESBL- and AmpC ß-lactamase-producing isolates. CONCLUSIONS: The confirmation of ESBL and/or AmpC ß-lactamase production can support the selection of an adequate antibiotic drug therapy. Despite a harmonized CLSI and EUCAST 'report as found' strategy for cephalosporins and ESBL-producing isolates, AST interpretation according to the CLSI 2013 and EUCAST 2013 guidelines shows significant differences in susceptibility rates for mainstay cephalosporins such as cefepime, ceftazidime and cefotaxime. Thus, further harmonization of clinical breakpoints is warranted.
