Abstract 3241: Children with acute lymphoblastic leukemia have increased arginase 2 at birth, implicating immunosuppression in leukemogenesis
Authors: Nielsen Amalie B. , Zhou Mi , Smith Adam de , McCoy Lucie , Hansen Helen , Bracci Paige , Morimoto Libby , Kogan Scott , Metayer Catherine , Ma Xiaomei , Wiemels Joseph 
Published: August 2018

Background: Epidemiologic evidence points to a role for infection and immune development in childhood acute lymphoblastic leukemia (ALL). Emerging evidence suggests that in utero immunosuppressive processes, along with immaturity at birth, cause immune hyporesponsiveness to commensal microbes and susceptibility to early childhood infections. A key regulator of active immunosuppression within the neonatal environment is arginase 2, which is produced by CD71+ erythroid cells and myeloid-derived suppressor cells. Arginase-dependent arginine depletion is suspected to aggravate both infections and tumor growth (the latter in adult settings) due to suppressed T-cell function by downregulation of TCR-CD3ζ. Studies have shown that immune vulnerability of the preterm neonate is critically related to arginase-dependent arginine depletion, but none have investigated this neonatal immunosuppression in relation to ALL.

Methods: Children were identified via California Cancer and Vital Statistics Registries, and their neonatal dried bloodspots derived from the California Genetic Disease Screening Program. Children were born in California between 1999 and 2009, with ALL cases being 0-15 years of age at diagnosis. 137 ALL cases and 500 controls (frequency matched on birthdate, gender, and ethnicity) were analyzed. Arginase 2 levels were measured using enzyme-linked immunosorbent assay (ELISA), with total serum-protein levels measured using the Pierce BCA protein assay. Arginase 2 levels in the analyses were adjusted for total serum protein and analyzed both as a continuous variable and as quartiles based on the distribution among controls. Adjusted unconditional logistic regression was used to estimate odds ratios (OR) for the association between neonatal arginase 2 and ALL with assay plate variance structure accounted for using cluster methods.

Results: Arginase 2 levels in neonatal dried blood spots were significantly higher among cases with ALL than controls (OR = 1.36, 95% CI: 1.02-1.80, p = 0.03). The highest quartile of arginase 2 levels differed significantly from the lowest (OR = 1.81, 95% CI: 1.04-3.41, p = 0.03), while the intermediate quartiles had a trend towards higher arginase 2 levels (p for trend: 0.02).

Conclusions: Our findings suggest that children with ALL have significantly higher immunosuppression at birth due to increased arginase 2. A high neonatal level of this enzyme, an important downregulator of T-cell activity, may lead to altered immune responses to antigenic stimulation and infection during early childhood and potentially impact the immune system's capability to react against nascent cancer. In addition to previously discovered prenatal mutations, this new finding of an immunosuppressed environment at birth contributes to our understanding of early events in the development of ALL.

Citation Format: Amalie B. Nielsen, Mi Zhou, Adam de Smith, Lucie McCoy, Helen Hansen, Paige Bracci, Libby Morimoto, Scott Kogan, Catherine Metayer, Xiaomei Ma, Joseph Wiemels. Children with acute lymphoblastic leukemia have increased arginase 2 at birth, implicating immunosuppression in leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3241.