P2X7A and B as novel biomarkers of acute myeloid leukemia response to chemotherapy and innovative therapeutic targets for the disease

The ATP gated ion channel P2X7 is attracting increasing attention for its role in oncogenesis as it is involved both in cancer cell transformation and in immune cells tumour crosstalk [1]. Nine different human P2X7 splice variants have been identified, among which the classical P2X7A receptor and the P2X7B isoform, which lacks the P2X7 large pore forming activity but still gives rise to a calcium channel and has been associated to cancer cell proliferation [2,3].Overexpression of P2X7 and a pro-apoptotic role of ATP was recently demonstrated in the blasts of acute myeloid leukaemia (AML) patients [4]; however, a characterization of the different splice variants was still missing. Here we investigated the mRNA levels of P2X7A and B in 92 patients affected with AML or myelodysplastic syndrome (MDS), a pre-cancerous condition often leading toAMLdevelopment. Interestingly, both P2X7A andBwere overexpressed inAMLfirstly diagnosed patients as compared to MDS, suggesting that both receptors could be involved in the progression of the disease. Moreover, when subdividing the AML population in firstly diagnosed untreated (61), relapsing (11) and remitting (5) patients, we retrieved a differential expression of P2X7B versus P2X7A. In relapsing patients, which are presented with a return of the pathology after chemotherapy, while P2X7A tends to decrease, P2X7B is significantly increasing. On the contrary, when comparing de novo with remitting patients both P2X7A and B show a tendency to decrease. These data suggest that P2X7B expressing blasts could be resistant to chemotherapy and responsible for the relapse of AML. In accordanceHEK293 cells expressing P2X7B showed increased resistance to death induced by danourubicin, possibly the most used chemotherapic in AML treatment, as compared to mock transfected or P2X7A expressing cells. In an AML xenograft model both daunorubicin and the P2X7 antagonist AZ10606120 significantly reduced tumour cell growth but the co-administration of the two drugs proved more efficacious. Of interest while danourubicin alone caused an increase in P2X7B expression in the tumour the co-treatment with the P2X7 blocking drug was able to reduce P2X7B levels. Taken together our data suggest that both P2X7A and P2X7B isoforms could be useful prognostic markers and potential therapeutic targets in AML.