P2X7 Receptor in Hematological Malignancies

Abstract

The P2X7 receptor is an ion channel gated by the nucleotide ATP, known for its role in immune responses and recently emerging as a critical onco-promoting factor. Lymphocytes, myeloid cells, and their precursors were among the first cells proved to express a functional P2X7 receptor; therefore, it is not surprising that lymphoproliferative and myeloproliferative diseases, also known as hematological malignancies, were shown to be related in their insurgence and progression to P2X7 alterations. Here, we overview established and recent literature relating P2X7 with the biological mechanisms underlying leukemias, lymphomas, and multiple myeloma development. Particular attention is paid to studies published in the very recent past correlating P2X7 with ATP concentration in the leukemic microenvironment and P2X7 overexpression to acute myeloid leukemia aggressiveness and response to chemotherapy. The described literature strongly suggests that P2X7 and its genetic variants could be regarded as potential new biomarkers in hematological malignancies and that both P2X7 antagonists and agonists could emerge as new therapeutic tools alone or in combination with traditional chemotherapy.

Keywords: ATP; P2X7 receptor; leukemia; lymphoma; multiple myeloma.

FIGURE 1

Schematic representation of P2X7 reported activities in myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), B chronic lymphocytic leukemia (B-CLL), lymphoma, and multiple myeloma. P2X7 is upregulated, progressing from progenitor stem cells to MDS and overt AML, further increasing its expression in mixed-lineage leukemia (MLL)-rearranged AML. Chemotherapy leads to a reduction of P2X7 isoform A, which via macropore formation facilitates daunorubicin cytotoxicity while upregulating P2X7 isoform B that protects leukemic blasts from cell death. P2X7 expression rises in aggressive B-CLL and associates with chromosome 12 trisomy and a reduction in NLRP3 (NOD-, LRR,- and pyrin domain-containing protein 3) expression. In lymphoma, P2X7 blockade reduces metastasis to peripheral lymph nodes. In multiple myeloma, P2X7 antagonism could lead to pain reduction.

FIGURE 2

(A) The pmeLUC probe allows for live imaging of ATP in the leukemic microenvironment (for detailed methods, see De Marchi et al., 2020). Note the prevalent concentration of ATP and leukemic cells, injected 7 days before the acquisition in the right hind, at the spinal column, suggesting a tropism of acute myeloid leukemia (AML) cells to the backbone. (B) Table summarizing studies reporting P2X7 genetic association with hematological malignancies and efficacy of receptor’s blockade/activation in in vivo murine models.