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An alternative CYB5A transcript is expressed in aneuploid ALL and enriched in relapse.
Bartsch, Lorenz; Schroeder, Michael P; Hänzelmann, Sonja; Bastian, Lorenz; Lázaro-Navarro, Juan; Schlee, Cornelia; Tanchez, Jutta Ortiz; Schulze, Veronika; Isaakidis, Konstandina; Rieger, Michael A; Gökbuget, Nicola; Eckert, Cornelia; Serve, Hubert; Horstmann, Martin; Schrappe, Martin; Brüggemann, Monika; Baldus, Claudia D; Neumann, Martin.
Afiliação
  • Bartsch L; Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, 12203, Berlin, Germany. lorenz.bartsch@charite.de.
  • Schroeder MP; Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, 12203, Berlin, Germany.
  • Hänzelmann S; Research Institute Children's Cancer Center, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg, 20251, Hamburg, Germany.
  • Bastian L; German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Lázaro-Navarro J; German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
  • Schlee C; Department of Hematology and Oncology, University Hospital Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany.
  • Tanchez JO; German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Schulze V; German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
  • Isaakidis K; Department of Pediatric Hematology/Oncology, Charité, University Hospital Berlin, Campus Rudolf Virchow, 13353, Berlin, Germany.
  • Rieger MA; Core Unit Genomics, Berlin Institute of Health, 13353, Berlin, Germany.
  • Gökbuget N; Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, 12203, Berlin, Germany.
  • Eckert C; Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, 12203, Berlin, Germany.
  • Serve H; Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, 12203, Berlin, Germany.
  • Horstmann M; German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Schrappe M; German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
  • Brüggemann M; Department of Medicine, Department of Hematology/Oncology, Goethe University Hospital, 60590, Frankfurt/M, Germany.
  • Baldus CD; Frankfurt Cancer Institute, 60590, Frankfurt/M, Germany.
  • Neumann M; German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
BMC Genom Data ; 23(1): 30, 2022 04 18.
Article em En | MEDLINE | ID: mdl-35436854
ABSTRACT

BACKGROUND:

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogenous malignancy with poor prognosis in relapsed adult patients. The genetic basis for relapse in aneuploid subtypes such as near haploid (NH) and high hyperdiploid (HeH) BCP-ALL is only poorly understood. Pathogenic genetic alterations remain to be identified. To this end, we investigated the dynamics of genetic alterations in a matched initial diagnosis-relapse (ID-REL) BCP-ALL cohort. Here, we firstly report the identification of the novel genetic alteration CYB5Aalt, an alternative transcript of CYB5A, in two independent cohorts.

METHODS:

We identified CYB5alt in the RNAseq-analysis of a matched ID-REL BCP-ALL cohort with 50 patients and quantified its expression in various molecular BCP-ALL subtypes. Findings were validated in an independent cohort of 140 first diagnosis samples from adult BCP-ALL patients. Derived from patient material, the alternative open reading frame of CYB5Aalt was cloned (pCYB5Aalt) and pCYB5Aalt or the empty vector were stably overexpressed in NALM-6 cells. RNA sequencing was performed of pCYB5Aalt clones and empty vector controls followed by differential expression analysis, gene set enrichment analysis and complementing cell death and viability assays to determine functional implications of CYB5Aalt.

RESULTS:

RNAseq data analysis revealed non-canonical exon usage of CYB5Aalt starting from a previously undescribed transcription start site. CYB5Aalt expression was increased in relapsed BCP-ALL and its occurrence was specific towards the shared gene expression cluster of NH and HeH BCP-ALL in independent cohorts. Overexpression of pCYB5Aalt in NALM-6 cells induced a distinct transcriptional program compared to empty vector controls with downregulation of pathways related to reported functions of CYB5A wildtype. Interestingly, CYB5A wildtype expression was decreased in CYB5Aalt samples in silico and in vitro. Additionally, pCYB5Aalt NALM-6 elicited a more resistant drug response.

CONCLUSIONS:

Across all age groups, CYB5Aalt was the most frequent secondary genetic event in relapsed NH and HeH BCP-ALL. In addition to its high subgroup specificity, CYB5Aalt is a novel candidate to be potentially implicated in therapy resistance in NH and HeH BCP-ALL. This is underlined by overexpressing CYB5Aalt providing first evidence for a functional role in BCL2-mediated apoptosis.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Leucemia-Linfoma Linfoblástico de Células Precursoras B / Citocromos b5 Tipo de estudo: Prognostic_studies Limite: Adult / Humans Idioma: En Revista: BMC Genom Data Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Leucemia-Linfoma Linfoblástico de Células Precursoras B / Citocromos b5 Tipo de estudo: Prognostic_studies Limite: Adult / Humans Idioma: En Revista: BMC Genom Data Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha