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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

Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies

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  • Medientyp: E-Artikel
  • Titel: Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies
  • Beteiligte: 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
  • Erschienen: Springer Science and Business Media LLC, 2022
  • Erschienen in: Journal of Cancer Research and Clinical Oncology
  • Sprache: Englisch
  • DOI: 10.1007/s00432-021-03827-9
  • ISSN: 0171-5216; 1432-1335
  • Schlagwörter: Cancer Research ; Oncology ; General Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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<jats:italic>n</jats:italic> = 18, chronic eosinophilic leukemia not otherwise specified<jats:italic>n</jats:italic> = 9, lymphocyte-variant hypereosinophilia<jats:italic>n</jats:italic> = 2, myeloproliferative neoplasm with eosinophilia<jats:italic>n</jats:italic> = 2, eosinophilic granulomatosis with polyangiitis<jats:italic>n</jats:italic> = 11, reactive eosinophilia<jats:italic>n</jats:italic> = 3).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Contrary to published literature, we found no difference in the levels of the lncRNA<jats:italic>Morrbid</jats:italic>and its target<jats:italic>BIM</jats:italic>. Yet, we identified a near complete loss of expression of pro-apoptotic<jats:italic>PUMA</jats:italic>as well as a reduction in anti-apoptotic<jats:italic>BCL-2</jats:italic>. Accordingly,<jats:italic>BCL-2</jats:italic>inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast,<jats:italic>MCL1</jats:italic>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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our study shows that<jats:italic>MCL1</jats:italic>inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.</jats:p></jats:sec>