Ectonucleotidases in Blood Malignancies: A Tale of Surface Markers and Therapeutic Targets

Abstract

Leukemia develops as the result of intrinsic features of the transformed cell, such as gene mutations and derived oncogenic signaling, and extrinsic factors, such as a tumor-friendly, immunosuppressed microenvironment, predominantly in the lymph nodes and the bone marrow. There, high extracellular levels of nucleotides, mainly NAD+ and ATP, are catabolized by different ectonucleotidases, which can be divided in two families according to substrate specificity: on one side those that metabolize NAD+, including CD38, CD157, and CD203a; on the other, those that convert ATP, namely CD39 (and other ENTPDases) and CD73. They generate products that modulate intracellular calcium levels and that activate purinergic receptors. They can also converge on adenosine generation with profound effects, both on leukemic cells, enhancing chemoresistance and homing, and on non-malignant immune cells, polarizing them toward tolerance. This review will first provide an overview of ectonucleotidases expression within the immune system, in physiological and pathological conditions. We will then focus on different hematological malignancies, discussing their role as disease markers and possibly pathogenic agents. Lastly, we will describe current efforts aimed at therapeutic targeting of this family of enzymes.

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

“…eNAD is degraded by three main classes of specific ectoenzymes: CD38 and CD157 (62,63), ARTs (64), ENPP1 and CD73 (61,65,66). NADase, ENPP1 and CD73 can lead to the formation of adenosine (ADO), a potent immunosuppressant factor, independently of the activity of CD39 (61,67,68). Beside generating ADO, eNAD can be degraded to nicotinamide mononucleotide (NMN) by CD38, generating Nam which can cross plasma membranes and be re-converted to NAD through NAMPT and NMN adenylyltransferase (NMNAT) (69).…”

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

“…Moreover, metabolic adaptation is accompanied by increased generation and release in the extracellular space of intermediate products and co-factors such as nicotinamide adenine dinucleotide (NAD + ) and adenosine triphosphate (ATP) [121] that can be further metabolized to adenosine (discussed in the next paragraph) [122]. In particular, NAD + is critical in a number of metabolic and biological processes, being used as a redox coenzyme by several dehydrogenases, and as a co-substrate by various NAD-consuming enzymes, such as mono-or poly-ADP ribosyltransferases and sirtuins [123].…”

Host CD39 Deficiency Affects Radiation-Induced Tumor Growth Delay and Aggravates Radiation-Induced Normal Tissue Toxicity

“…Accordingly, CD203a/PC-1 expression was found to be rather low on lymphocytes, monocytes, and granulocytes of the bone marrow (123). In contrast to CD203a, a high CD38 expression on circulating monocytes has been described (56,124,125). Resident lung macrophages can also express CD38 (126,127).…”

“…In this non-canonical pathway, extracellular NAD + is metabolized into ADP ribose (ADPR) via the cyclic ADPR hydrolase (CD38). The product is further converted to AMP via the action of ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1 or CD203a/PC-1) (53)(54)(55)(56). Moreover, CD203a is capable to hydrolyze ATP, NAD + , and ADPR directly to produce AMP, but CD203a has a (significantly) lower affinity to ATP (57, 58).…”