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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.

journal_name

Blood

journal_title

Blood

authors

Mussai F,Egan S,Higginbotham-Jones J,Perry T,Beggs A,Odintsova E,Loke J,Pratt G,U KP,Lo A,Ng M,Kearns P,Cheng P,De Santo C

doi

10.1182/blood-2014-09-600643

subject

Has Abstract

pub_date

2015-04-09 00:00:00

pages

2386-96

issue

15

eissn

0006-4971

issn

1528-0020

pii

blood-2014-09-600643

journal_volume

125

pub_type

杂志文章

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