Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, China.
Haematologica. 2021 May 1;106(5):1278-1289. doi: 10.3324/haematol.2019.243360.
Nucleotides mediate intercellular communication by activating purinergic receptors and take part in various physiological and pathological processes. Abnormal purinergic signaling plays important roles in malignant progression. P2X7, which belongs to the P2X family of purinergic receptors, is abnormally expressed in various types of malignancies including leukemia. However, its role and molecular mechanism in leukemia have not been elucidated. Here, we analyzed the correlation between P2X7 expression and AML clinical outcome; explored the role and mechanism of P2X7 in AML progression by using mouse acute myeloid leukemia (AML), nude mouse xenograft and patient-derived xenograft models. High levels of P2X7 expression were correlated with worse survival in AML. P2X7 was highly expressed in MLL-rearranged AML. Furthermore, P2X7 accelerated the progression of MLL-rearranged AML by both promoting cell proliferation and increasing leukemia stem cell (LSC) levels. Moreover, P2X7 caused upregulation of Pbx3 accounts for its pro-leukemic effects. The P2X7-Pbx3 pathway might also contribute to the progression of other types of leukemia as well as solid tumors with high levels of P2X7 expression. Our study provides new insights into the malignant progression caused by abnormal purinergic signaling.
核苷酸通过激活嘌呤能受体介导细胞间通讯，并参与各种生理和病理过程。异常的嘌呤能信号在恶性进展中起着重要作用。P2X7 属于嘌呤能受体 P2X 家族，在包括白血病在内的各种类型的恶性肿瘤中异常表达。然而，其在白血病中的作用和分子机制尚未阐明。在这里，我们分析了 P2X7 表达与 AML 临床结局的相关性；通过使用小鼠急性髓系白血病 (AML)、裸鼠异种移植和患者来源的异种移植模型，探讨了 P2X7 在 AML 进展中的作用和机制。高水平的 P2X7 表达与 AML 患者的生存预后较差相关。P2X7 在 MLL 重排的 AML 中高表达。此外，P2X7 通过促进细胞增殖和增加白血病干细胞 (LSC)水平，加速了 MLL 重排的 AML 的进展。此外，P2X7 导致 Pbx3 的上调，这是其促白血病作用的原因。P2X7-Pbx3 通路可能也有助于其他类型的白血病以及 P2X7 高表达的实体瘤的进展。我们的研究为异常嘌呤能信号引起的恶性进展提供了新的见解。
