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Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies.
Odinius, Timo O; Buschhorn, Lars; Wagner, Celina; Hauch, Richard T; Dill, Veronika; Dechant, Marta; Buck, Michele C; Shoumariyeh, Khalid; Moog, Philipp; Schwaab, Juliana; Reiter, Andreas; Brockow, Knut; Götze, Katharina; Bassermann, Florian; Höckendorf, Ulrike; Branca, Caterina; Jost, Philipp J; Jilg, Stefanie.
Afiliación
  • Odinius TO; Clinic and Policlinic for Internal Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.
  • Buschhorn L; Centre for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
  • Wagner C; Clinic and Policlinic for Internal Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.
  • Hauch RT; Centre for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
  • Dill V; Clinic and Policlinic for Internal Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.
  • Dechant M; Centre for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
  • Buck MC; Clinic and Policlinic for Internal Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.
  • Shoumariyeh K; Clinic and Policlinic for Internal Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.
  • Moog P; Centre for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
  • Schwaab J; Clinic and Policlinic for Internal Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.
  • Reiter A; Centre for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
  • Brockow K; Clinic and Policlinic for Internal Medicine III, School of Medicine, Technical University of Munich, Munich, Germany.
  • Götze K; Department of Medicine I, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg Im Breisgau, Germany.
  • Bassermann F; German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg im Breisgau, Germany.
  • Höckendorf U; Department of Nephrology, Clinic and Policlinic for Internal Medicine II, School of Medicine, Technical University of Munich, Munich, Germany.
  • Branca C; Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.
  • Jost PJ; Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.
  • Jilg S; Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany.
J Cancer Res Clin Oncol ; 148(2): 331-340, 2022 Feb.
Article en En | MEDLINE | ID: mdl-34654952
PURPOSE: Hypereosinophilia represents a heterogenous group of severe medical conditions characterized by elevated numbers of eosinophil granulocytes in peripheral blood, bone marrow or tissue. Treatment options for hypereosinophilia remain limited despite recent approaches including IL-5-targeted monoclonal antibodies and tyrosine kinase inhibitors. METHODS: To understand aberrant survival patterns and options for pharmacologic intervention, we characterized BCL-2-regulated apoptosis signaling by testing for BCL-2 family expression levels as well as pharmacologic inhibition using primary patient samples from diverse subtypes of hypereosinophilia (hypereosinophilic syndrome n = 18, chronic eosinophilic leukemia not otherwise specified n = 9, lymphocyte-variant hypereosinophilia n = 2, myeloproliferative neoplasm with eosinophilia n = 2, eosinophilic granulomatosis with polyangiitis n = 11, reactive eosinophilia n = 3). RESULTS: Contrary to published literature, we found no difference in the levels of the lncRNA Morrbid and its target BIM. Yet, we identified a near complete loss of expression of pro-apoptotic PUMA as well as a reduction in anti-apoptotic BCL-2. Accordingly, BCL-2 inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast, MCL1 inhibition using S63845 specifically decreased the viability of bone marrow progenitor cells in patients with hypereosinophilia. In patients diagnosed with Chronic Eosinophilic Leukemia (CEL-NOS) or Myeloid and Lymphatic Neoplasia with hypereosinophilia (MLN-Eo) repression of survival was specifically powerful. CONCLUSION: Our study shows that MCL1 inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome Hipereosinofílico / Proteínas Proto-Oncogénicas c-bcl-2 / Eosinófilos Tipo de estudio: Observational_studies Límite: Humans Idioma: En Revista: J Cancer Res Clin Oncol Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome Hipereosinofílico / Proteínas Proto-Oncogénicas c-bcl-2 / Eosinófilos Tipo de estudio: Observational_studies Límite: Humans Idioma: En Revista: J Cancer Res Clin Oncol Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania