Francis Mussai
Arginine dependence of acute myeloid leukaemia blast proliferation: a novel therapeutic target
Mussai, Francis; Egan, Sharon A.; Higginbotham-Jones, Joseph; Perry, Tracey; Beggs, Andrew; Odintsova, Elena; Loke, Justin; Pratt, Guy; Pong U, Kin; Lo, Anthony; Ng, Margaret; Kearns, Pamela R.; Cheng, Paul; De Santo, Carmela
Authors
Sharon A. Egan
Joseph Higginbotham-Jones
Tracey Perry
Andrew Beggs
Elena Odintsova
Justin Loke
Guy Pratt
Kin Pong U
Anthony Lo
Margaret Ng
Pamela R. Kearns
Paul Cheng
Carmela De Santo
Abstract
Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML.
Citation
Mussai, F., Egan, S. A., Higginbotham-Jones, J., Perry, T., Beggs, A., Odintsova, E., …De Santo, C. (2015). Arginine dependence of acute myeloid leukaemia blast proliferation: a novel therapeutic target. Blood, 125(15), https://doi.org/10.1182/blood-2014-09-600643
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 11, 2015 |
Online Publication Date | Feb 20, 2015 |
Publication Date | Apr 9, 2015 |
Deposit Date | Nov 4, 2016 |
Publicly Available Date | Nov 4, 2016 |
Journal | Blood |
Print ISSN | 0006-4971 |
Electronic ISSN | 1528-0020 |
Publisher | American Society of Hematology |
Peer Reviewed | Peer Reviewed |
Volume | 125 |
Issue | 15 |
DOI | https://doi.org/10.1182/blood-2014-09-600643 |
Keywords | Arginase depletion, BCT-100 pegylated recombinant human arginase, AML blasts |
Public URL | https://nottingham-repository.worktribe.com/output/749979 |
Publisher URL | http://www.bloodjournal.org/content/125/15/2386 |
Additional Information | "This research was originally published in Blood. Francis Mussai, Sharon Egan, Joseph Higginbotham-Jones, Tracey Perry, Andrew Beggs, Elena Odintsova, Justin Loke, Guy Pratt, Kin Pong U, Anthony Lo, Margaret Ng, Pamela Kearns, Paul Cheng and Carmela De Santo. Arginine dependence of acute myeloid leukaemia blast proliferation: a novel therapeutic target. Blood. 2015 ;Vol 125 : p. 2386-2396 . © the American Society of Hematology. |
Contract Date | Nov 4, 2016 |
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