Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target
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Acute Myeloid Leukaemia (AML) is one of the most common acute leukaemias 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 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 arginosuccinate synthase (ASS) and ornithine transcarbamylase (OTC), 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, and depletion of arginine with BCT-100 of clinical value in the treatment of AML.
|Number of pages||11|
|Early online date||20 Feb 2015|
|Publication status||Published - 9 Apr 2015|