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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

Francis Mussai

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.

Journal Article Type Article
Publication Date Apr 9, 2015
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 125
Issue 15
APA6 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
DOI https://doi.org/10.1182/blood-2014-09-600643
Keywords Arginase depletion, BCT-100 pegylated recombinant human arginase, AML blasts
Publisher URL http://www.bloodjournal.org/content/125/15/2386
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
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.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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