Journal article

Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL

Marco Haselager, Karoline Kielbassa, Johanna ter Burg, Danique JC Bax, Stacey M Fernandes, Jannie Borst, Constantine Tam, Francesco Forconi, Giorgia Chiodin, Jennifer R Brown, Julie Dubois, Arnon P Kater, Eric Eldering

Blood | AMER SOC HEMATOLOGY | Published : 2020

Abstract

Chronic lymphocytic leukemia (CLL) cells cycle between lymph node (LN) and peripheral blood (PB) and display major shifts in Bcl-2 family members between those compartments. Specifically, Bcl-XL and Mcl-1, which are not targeted by the Bcl-2 inhibitor venetoclax, are increased in the LN. Since ibrutinib forces CLL cells out of the LN, we hypothesized that ibrutinib may thereby affect expression of Bcl-XL and Mcl-1 and sensitize CLL cells to venetoclax. We investigated expression of Bcl-2 family members in patients under ibrutinib or venetoclax treatment combined with dissecting functional interactions of Bcl-2 family members in an in vitro model for venetoclax resistance. In the PB, recent L..

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Grants

Awarded by PPP Allowance by Top Sector Life Sciences Health


Funding Acknowledgements

This work was supported by a grant from the European Research Area Network (ERA-NET) on Translational Cancer Research (TRANSCAN 2) in support of the consortium Fighting Resistance in CLL. M.H. was funded by Blaauboer Fund via the AMC Foundation. K.K. was financed by the PPP Allowance made available by Top Sector Life Sciences & Health under project number LSHM18055-SGF. For more information: www.target-to-b.nl.