Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models

P2X7 Receptor in Hematological Malignancies

“…Similar results were obtained when silencing the P2X7 receptor in both leukemic cell lines and leukemia-initiating stem cells (Feng et al, 2020;He et al, 2020), thus reproducing the effect of P2X7 ablation in solid cancer models (Adinolfi et al, 2012b). On the contrary, P2X7 overexpression increased the proliferative potential of leukemic blasts and the number of leukemia-initiating lymphocytes central for AML relapse (Feng et al, 2020;He et al, 2020). Various signaling proteins and circulating cytokines, activated by the P2X7 receptor, associate with increased tumorigenic activity in AML.…”

“…Consistently, administration of different P2X7 antagonists caused a significant reduction in AML growth and dissemination (De Marchi et al, 2019;He et al, 2020;Pegoraro et al, 2020), as well as an increase in overall survival (He et al, 2020) in various murine models of the disease, obtained both in xenotransplanted and syngeneic mice, thus confirming the efficacy of P2X7 blockade both on human leukemic cells and in hosts with a functional immune system. Similar results were obtained when silencing the P2X7 receptor in both leukemic cell lines and leukemia-initiating stem cells (Feng et al, 2020;He et al, 2020), thus reproducing the effect of P2X7 ablation in solid cancer models (Adinolfi et al, 2012b). On the contrary, P2X7 overexpression increased the proliferative potential of leukemic blasts and the number of leukemia-initiating lymphocytes central for AML relapse (Feng et al, 2020;He et al, 2020).…”

“…These data are supported by the analysis of different genetic databases and patients' specimens demonstrating an upregulation of P2X7 in AML cohorts (Chong et al, 2010;Salvestrini et al, 2017;Feng et al, 2020;He et al, 2020). Consistently, high P2X7 levels are associated with reduced overall survival (He et al, 2020). Moreover, Feng et al (2020) revealed an increased expression of P2X7 in AML patients carrying chromosomal translocations of mixed-lineage leukemia (MLL) genes (MLL-rearranged AML), which are generally presented with unfavorable clinical outcomes (Figure 1).…”

“…the levels of both P2X7 isoforms were upregulated in AML compared to MDS (Pegoraro et al, 2020), thus suggesting a role for P2X7 in malignant transformation (Pegoraro et al, 2020). These data are supported by the analysis of different genetic databases and patients' specimens demonstrating an upregulation of P2X7 in AML cohorts (Chong et al, 2010;Salvestrini et al, 2017;Feng et al, 2020;He et al, 2020). Consistently, high P2X7 levels are associated with reduced overall survival (He et al, 2020).…”

“…Overexpression and increased function of P2X7 were also reported in acute lymphoblastic and chronic myeloid leukemia patients (Zhang et al, 2004;Chong et al, 2010). However, the highest number of studies present in literature is related to P2X7's role in AML of infancy and adulthood and to myelodysplastic syndromes (MDSs) (Zhang et al, 2004;Chong et al, 2010;Salvestrini et al, 2012Salvestrini et al, , 2017Lecciso et al, 2017;Feng et al, 2020;He et al, 2020;Pegoraro et al, 2020). AML is a severe hematological disease characterized by clonal expansion of hematopoietic stem cells, which, in some cases, can arise from a preexisting MDS (Richard-Carpentier and DiNardo, 2019).…”