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Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1278-1289
Acute Myeloid Leukemia
P2X7 promotes the progression of MLL-AF9-induced acute myeloid leukemia by upregulation of Pbx3
Wenli Feng,# Xiao Yang,# Lina Wang, Rong Wang, Feifei Yang, Hao Wang, Xiaoli Liu, Qian Ren, Yingchi Zhang, Xiaofan Zhu and Guoguang Zheng
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
#WF and XY contributed equally as co-first authors.
ABSTRACT
Nucleotides mediate intercellular communication by activating purinergic receptors and take part in various physiological and pathological processes. Abnormal purinergic signaling plays impor- tant roles in malignant progression. P2X7, which belongs to the P2X family of purinergic receptors, is abnormally expressed in various types of malig- nancies including leukemia. However, its role and molecular mechanism of action in leukemia have not been elucidated. Here, we analyzed the corre- lation between P2X7 expression and clinical outcome in acute myeloid leukemia (AML); we explored the role and mechanism of P2X7 in AML progression by using mouse 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 and accelerated the progression of this type of AML both by promoting cell proliferation and by increasing leukemia stem cells. Furthermore, P2X7 caused upregulation of Pbx3 which might account 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 progression of malignancy caused by abnormal purinergic signaling.
Introduction
Aberrant cell signaling, caused by both genetic and epigenetic abnormalities, plays a vital role in the pathogenesis and development of malignancies.1 Nucleotides, which have been suggested to be extracellular messengers for decades, play important roles under various physiological and pathological condi- tions by activating purinergic receptors.2 P2X7, the latest cloned member of the P2X family of purinergic receptors, is abnormally expressed in solid tumors.3 Calcium- triggered activation of the PI3K/AKT pathway and downstream ERK1/2 or P38 has been suggested to be involved in P2X7-dependent growth and invasiveness in solid tumors.4,5 Subsequently, the increased release of tumor necrosis factor-α, vascular endothelial growth factor, matrix metalloproteinases or substance P was found to favor the proliferation, infiltration and metastasis of tumor cells. Abnormal expres- sion of P2X7 was detected in patients with leukemia, especially those with relapsed acute leukemia and evolutive B-cell chronic lymphocytic leukemia (CLL).6-8 Furthermore, a hyposensitive P2X7 mutant was cloned from leukemia cells.9,10 These results imply that abnormal P2X7 signaling plays a role in leukemia. We recently demonstrated that overexpression of P2X7 could not transform normal hematopoietic stem/progenitor cells into leukemia cells.11 However, the role and mechanism of action of P2X7 in leukemia progression have not been elucidated.
Diverse endogenous and microenvironmental abnormalities contribute to the pathogenesis and progression of highly heterogeneous leukemias.12-15 Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are detected in nearly 80% of infants and 10% of adults with acute leukemia, and these patients often have unfavorable clinical outcomes.16 Although more than 70 partners have
Correspondence:
GUOGUANG ZHENG
zhengggtjchn@aliyun.com
Received: November 19, 2019. Accepted: March 6, 2020. Pre-published: March 12, 2020.
https://doi.org/10.3324/haematol.2019.243360
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