TY - JOUR
T1 - Arginine dependence of acute myeloid leukemia blast proliferation
T2 - a novel therapeutic target
AU - Mussai, Francis
AU - Egan, Sharon
AU - Higginbotham-Jones, Joseph
AU - Perry, Tracey
AU - Beggs, Andrew
AU - Odintsova, Elena
AU - Loke, Justin
AU - Pratt, Guy
AU - U, Kin Pong
AU - Lo, Anthony
AU - Ng, Margaret
AU - Kearns, Pamela
AU - Cheng, Paul
AU - De Santo, Carmela
N1 - Copyright © 2015 American Society of Hematology.
PY - 2015/4/9
Y1 - 2015/4/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84927547048&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-09-600643
DO - 10.1182/blood-2014-09-600643
M3 - Article
C2 - 25710880
SN - 0006-4971
VL - 125
SP - 2386
EP - 2396
JO - Blood
JF - Blood
IS - 15
ER -