title: Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target.
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.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Francis
authors.initials: F
authors.lastname: Mussai
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Sharon
authors.initials: S
authors.lastname: Egan
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Joseph
authors.initials: J
authors.lastname: Higginbotham-Jones
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Tracey
authors.initials: T
authors.lastname: Perry
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: Beggs
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Elena
authors.initials: E
authors.lastname: Odintsova
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Justin
authors.initials: J
authors.lastname: Loke
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.affiliation: Bio-cancer Treatment International Ltd, Hong Kong Science Park, Shatin, New Territories, Hong Kong; and.
authors.forename: Kin Pong
authors.initials: KP
authors.lastname: U
authors.affiliation: Department of Anatomic Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lo
authors.affiliation: Department of Anatomic Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ng
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Pamela
authors.initials: P
authors.lastname: Kearns
authors.affiliation: Bio-cancer Treatment International Ltd, Hong Kong Science Park, Shatin, New Territories, Hong Kong; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Cheng
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Carmela
authors.initials: C
authors.lastname: De Santo
mesh_terms: D000293:Adolescent; D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001119:Arginase / Q000627:therapeutic use*; D001120:Arginine / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000627:therapeutic use; D057487:Enzyme Therapy; D005260:Female; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016513:Mice, SCID; D008875:Middle Aged; D011994:Recombinant Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D003561:Cytarabine; D001120:Arginine; D001119:Arginase