Arginase-mediated “field” defects in AML

In this issue of Blood, Mussai et al report on the ability of acute myeloid leukemia (AML) blasts to inhibit the immune system and hematopoiesis through aberrantly high levels of arginase II activity.¹  AML is a clinically, genetically, and epigenetically heterogeneous disease.²  Both epigenetic and genetic aberrations in AML blasts have been used to understand mechanisms of leukemia growth and predict patients’ outcomes, as well as assign them to different treatment approaches. However, the majority of patients treated with chemotherapy and/or molecular targeting agents continue to die of their disease. Stem cell transplantation (SCT) has been proven effective in curing AML by allowing for the administration of otherwise myeloablative and toxic doses of chemotherapy and for reconstitution of an effective immune system from the donor graft that, in turn, contributes to the eradication of resistant clonal cell subpopulations. These populations may include those with high self-renewal ability: the so-called leukemia stem (or initiating) cells. However, even following SCT, patients may relapse and die of their disease, underlying the complexity of AML biology and of the mechanisms of disease resistance.

To date, the main focus of AML studies has been on the genetic and epigenetic features of the blasts and how these characteristics relate to mechanisms leading to the arrest of hematopoietic differentiation and the ability to proliferate and survive even after administration of cytotoxic compounds. However, an increasing number of studies now emphasize the biologic significance and potential clinical relevance of the microenvironment in AML.^3,4  The findings by Mussai et al¹  further support this view by showing that aberrant arginase II activity contributes to leukemogenesis via suppression of T lymphocyte activity through polarization of monocytes into a suppressive M2-like phenotype and direct inhibition of the hematopoietic activity, which in turn may contribute to pancytopenia and marrow failure observed in AML. The role of arginase I in mechanisms of immunosuppression through myeloid-derived suppressor cells has been previously recognized,^5,6  whereas the activity of arginase II leading to an aberrant microenvironment is an original observation that reemphasizes the potential of myeloid blasts to create “field defects” and “niches” that allow for malignant growth and survival.

Several questions remain to be addressed to fully understand and harness the activity of myeloid blasts on the microenvironment, which could be the next frontier for molecularly targeted therapies in AML: What is the relationship between AML genotypes and the plasma arginase activity? Do high levels of arginase activity correlate with the presence of unfavorable AML cytogenetic and molecular features? Are residual blasts in patients receiving SCT still able to produce serum arginases, thereby inhibiting the host immune system and hematopoiesis, and in turn causing disease relapse? Are levels of arginase activity able to predict treatment failure, and can they be used as surrogate markers for minimal residual disease?

Ultimately, the answers to these questions will help us understand the clinical relevance of the findings by Mussai et al and whether determination of arginase levels at diagnosis and at regular follow-ups should be incorporated into the clinical evaluation of patients with AML. The development of novel treatment approaches for AML that include effective and nontoxic arginase inhibitors could eventually be pursued to improve the clinical outcome of patients with AML who have unfavorable clinical (ie, age, secondary disease) and genetic (cytogenetics, gene mutations, aberrant gene and microRNA expression) features.