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Cancer Science

Cancer Science

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Suppression of multiple anti-apoptotic BCL2 family proteins recapitulates the effects of JAK2 inhibitors in JAK2V617F driven myeloproliferative neoplasms

Published:22 November 2021 DOI: 10.1111/cas.15210 PMID: 34808021
Hisashi Takei, Juan Luiz Coelho-Silva, Cristina Tavares Leal, Adriana Queiroz Arantes Rocha, Thiago Mantello Bianco, Robert S. Welner, Yuta Mishima, Ikei S. Kobayashi, Ann Mullally, Keli Lima, Jo?o Agostinho Machado-Neto, Susumu S. Kobayashi, Lorena Lobo de Figueiredo-Pontes

Abstract

Several lines of research suggest that Bcl-xL-mediated anti-apoptotic effects may contribute to the pathogenesis of myeloproliferative neoplasms driven by JAK2V617F and serve as therapeutic target. Here, we used a knock-in JAK2V617F mouse model and confirmed that Bcl-xL was overexpressed in erythroid progenitors. The myeloproliferative neoplasm (MPN)-induced phenotype in the peripheral blood by conditional knock-in of JAK2V617F was abrogated by conditional knockout of Bcl2l1, which presented anemia and thrombocytopenia independently of JAK2 mutation status. Mx1-Cre Jak2V617W/VF/Bcl2l1f/f mice presented persistent splenomegaly as a result of extramedullary hematopoiesis and pro-apoptotic stimuli in terminally differentiated erythroid progenitors. The pan-BH3 mimetic inhibitor obatoclax showed superior cytotoxicity in JAK2V617F cell models, and reduced clonogenic capacity in ex vivo assay using Vav-Cre Jak2V617F bone marrow cells. Both ruxolitinib and obatoclax significantly reduced spleen weights in a murine Jak2V617F MPN model but did not show additive effect. The tumor burden reduction was observed with either ruxolitinib or obatoclax in terminal differentiation stage neoplastic cells but not in myeloid-erythroid precursors. Therefore, disrupting the BCL2 balance is not sufficient to treat MPN at the stem cell level, but it is certainly an additional option for controlling the critical myeloid expansion of the disease.

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ABT-199 1257044-40-8 C45H50ClN7O7S 534 suppliers $12.00-$4766.80
ABT-199 1257044-40-8 C45H50ClN7O7S 534 suppliers $12.00-$4766.80
ABT-199 1257044-40-8 C45H50ClN7O7S 534 suppliers $12.00-$4766.80
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