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Inhibition of HOX/PBX dimer formation leads to necroptosis in acute myeloid leukemia cells

Alharbi, Raed A.; Pandha, Hardev S.; Simpson, Guy R.; Pettengell, Ruth; Poterlowicz, Krzysztof; Thompson, Alexander; Harrington, Kevin; El-Tanani, Mohamed; Morgan, Richard

Authors

Raed A. Alharbi

Hardev S. Pandha

Guy R. Simpson

Ruth Pettengell

Krzysztof Poterlowicz

Kevin Harrington

Mohamed El-Tanani

Richard Morgan



Abstract

The HOX genes encode a family of transcription factors that have key roles in both development and malignancy. Disrupting the interaction between HOX proteins and their binding partner, PBX, has been shown to cause apoptotic cell death in a range of solid tumors. However, despite HOX proteins playing a particularly significant role in acute myeloid leukemia (AML), the relationship between HOX gene expression and patient survival has not been evaluated (with the exception of HOXA9), and the mechanism by which HOX/PBX inhibition induces cell death in this malignancy is not well understood. In this study, we show that the expression of HOXA5, HOXB2, HOXB4, HOXB9, and HOXC9, but not HOXA9, in primary AML samples is significantly related to survival. Furthermore, the previously described inhibitor of HOX/PBX dimerization, HXR9, is cytotoxic to both AML-derived cell lines and primary AML cells from patients. The mechanism of cell death is not dependent on apoptosis but instead involves a regulated form of necrosis referred to as necroptosis. HXR9-induced necroptosis is enhanced by inhibitors of protein kinase C (PKC) signaling, and HXR9 combined with the PKC inhibitor Ro31 causes a significantly greater reduction in tumor growth compared to either reagent alone.

Citation

Alharbi, R. A., Pandha, H. S., Simpson, G. R., Pettengell, R., Poterlowicz, K., Thompson, A., …Morgan, R. (2017). Inhibition of HOX/PBX dimer formation leads to necroptosis in acute myeloid leukemia cells. Oncotarget, 8(52), https://doi.org/10.18632/oncotarget.20023

Journal Article Type Article
Acceptance Date Jun 26, 2017
Publication Date Aug 7, 2017
Deposit Date Feb 13, 2018
Publicly Available Date Feb 13, 2018
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 8
Issue 52
DOI https://doi.org/10.18632/oncotarget.20023
Keywords acute myeloid leukemia, HOX, HXR9, necroptosis, protein kinase C
Public URL http://eprints.nottingham.ac.uk/id/eprint/49748
Publisher URL https://doi.org/10.18632/oncotarget.20023
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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