Arginine dependence of acute myeloid leukaemia blast proliferation: a novel therapeutic target

Mussai, Francis and Egan, Sharon A. and Higginbotham-Jones, Joseph and Perry, Tracey and Beggs, Andrew and Odintsova, Elena and Loke, Justin and Pratt, Guy and Pong U, Kin and Lo, Anthony and Ng, Margaret and Kearns, Pamela R. and Cheng, Paul and De Santo, Carmela (2015) Arginine dependence of acute myeloid leukaemia blast proliferation: a novel therapeutic target. Blood, 125 (15). pp. 2386-2396. ISSN 1528-0020

[img]
Preview
PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (1MB) | Preview

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.

Item Type: Article
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.
Keywords: Arginase depletion, BCT-100 pegylated recombinant human arginase, AML blasts
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Identification Number: 10.1182/blood-2014-09-600643
Depositing User: Egan, Sharon
Date Deposited: 04 Nov 2016 14:39
Last Modified: 16 Oct 2017 21:12
URI: http://eprints.nottingham.ac.uk/id/eprint/37630

Actions (Archive Staff Only)

Edit View Edit View