Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies
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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 Tilmann; 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.
In: J CANCER RES CLIN, Vol. 148, No. 2, 02.2022, p. 331-340.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies
AU - Odinius, Timo O
AU - Buschhorn, Lars
AU - Wagner, Celina
AU - Hauch, Richard Tilmann
AU - Dill, Veronika
AU - Dechant, Marta
AU - Buck, Michele C
AU - Shoumariyeh, Khalid
AU - Moog, Philipp
AU - Schwaab, Juliana
AU - Reiter, Andreas
AU - Brockow, Knut
AU - Götze, Katharina
AU - Bassermann, Florian
AU - Höckendorf, Ulrike
AU - Branca, Caterina
AU - Jost, Philipp J
AU - Jilg, Stefanie
N1 - © 2021. The Author(s).
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
U2 - 10.1007/s00432-021-03827-9
DO - 10.1007/s00432-021-03827-9
M3 - SCORING: Journal article
C2 - 34654952
VL - 148
SP - 331
EP - 340
JO - J CANCER RES CLIN
JF - J CANCER RES CLIN
SN - 0171-5216
IS - 2
ER -
