The ATP/P2X7 axis is a crucial regulator of leukemic initiating cells proliferation and homing and an emerging therapeutic target in acute myeloid leukemia

Acute myeloid leukemia (AML) is a severe malignancy of blood and bone marrow with a high relapse rate. The leading cause of recurrence is a particular cell population, referred to as leukemia-initiating cells (LICs), which self-renews and re-initiates leukemia after therapy. The mechanism that regulates LICs activity is not entirely understood. However, there is growing evidence that components of the bone marrow niche can sustain LICs proliferation. ATP is one of the molecules that accumulate in the tumor microenvironment and through the P2X7 receptor can regulate diferent oncogenic processes. In a recent study, He and colleagues correlated ATP and P2X7 receptors with leukemogenic activities of LICs [1]. Thanks to a new probe allowing for a live measure of ATP levels, they demonstrated that the nucleotide level is higher in the bone marrow of AML mice than in control animals. Furthermore, it preferentially accumulated in the endosteal niche where LICs reside and tend to home when injected in mice. Moreover, in both P2X7 receptor-knockout mice and mice transplanted with AML cells not expressing the P2X7 receptor, they observed that the leukemogenesis was slower than in control P2X7 receptor-expressing counterparts, indicating a central role for P2X7 in leukemia development. Accordingly, P2X7 receptors were found to be upregulated in AML patients and were correlated with reduced overall survival. The authors suggest that ATP/P2X7 receptor signaling drives LICs in the endosteal niche and promotes the process of LICs self-renewal through CREB (cAMP response element-binding protein) and PHGDH (posphoglycerate dehydrogenase) activity. Treatment with a specific P2X7 receptor antagonist reduced leukemia growth in mice transplanted with AML cells, encouraging a new therapeutic strategy with the P2X7 receptor as a pharmacological target.