scholarly journals Effects of Overexpressed P2X7 on Leukemia Progression in Mouse Acute Myeloid Leukemia Model

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5141-5141
Author(s):  
Wenli Feng ◽  
Xiao Yang ◽  
Rong Wang ◽  
Feifei Yang ◽  
Hao Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
High Level Expression ◽  
Innovation Fund ◽  
High Level ◽  
Acute Myeloid ◽  
Proliferation Potential

Abstract P2X7 is one of the P2X family ligand-gated ion channel receptors. High level expression of P2X7 is reported in various malignant cells. High level expression of P2X7 was also detected in leukemia patients, especially in relapsed cases. A hyposensitive P2X7 mutant, N187D P2X7, was cloned from leukemia cells. However, the role of P2X7 on the progression of leukemia was poorly understood. In the present study, we studied the effects of P2X7 receptor in acute myeloid leukemia mouse model. We established MLL-AF9 induced AML mouse model with high level expression of P2X7 (MA9-P2X7). High level of P2X7 significantly accelerated the progression of leukemia. Homing capability experiment demonstrated that MA9-P2X7 cells had lower homing potential. The apoptotic rate of freshly isolated leukemia cells had no significant difference between two groups. However, both in vitro culture experiments and in vivo BrdU incorporation assay demonstrated that MA9-P2X7 cells had enhanced proliferation potential, i.e. more S and G2/M phase cells but less G0/G1 phase cells. Moreover, upon treatment with Ara-C, though MA9-P2X7 cells were more sensitive to Ara-C, but the mice had shorter survival time. Furthermore, in vitro colony assay and limiting dilution transplantation experiments showed that MA9-P2X7 cells formed more colonies and had a 7.25-folds increase in LICs frequency. We also detected the expression of c-Kit, and the results showed that the majority of MA9-P2X7 cells were c-Kit+, whereas control cells have two populations and more than half of them were c-Kit-. Leukemia mice in MA9-P2X7 group had shorter survival time than those in the c-Kit+ control group. Our results suggested that leukemia cells overexpressing P2X7 possessed the characteristics of both greater proliferation potential and higher LICs frequency, which contributed to the accelerated progression of leukemia. This work was supported by grants 81570153, 81770183 and 81170511 from the National Natural Science Foundation of China (NSFC); programs 2016-I2M-2-006 and 2017-I2M-1-015 from the CAMS Innovation Fund for Medical Sciences (CIFMS); grant 17JCZDJC35000 from the Tianjin Natural Science Foundation; and Graduate Student Innovation Fund (2014-0710-1021) from Peking Union Medical College. Z.GG. is a recipient of the New Century Excellent Talents in University (NCET-08-0329). Disclosures No relevant conflicts of interest to declare.

scholarly journals Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

Blood ◽  
2016 ◽  
Vol 128 (3) ◽  
pp. 410-414 ◽  
Author(s):  
Ewa M. Kosciuczuk ◽  
Diana Saleiro ◽  
Barbara Kroczynska ◽  
Elspeth M. Beauchamp ◽  
Frank Eckerdt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Leukemia Cells ◽  
Key Points ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

Key Points Merestinib blocks Mnk kinase activity in acute myeloid leukemia cells. Merestinib suppresses human leukemic progenitors and exhibits potent antileukemic effects in a xenograft mouse model.

Rig-I Activates Expression of Interferon-Stimulated Genes (ISGs) and Inhibits the Proliferation of Acute Myeloid Leukemia Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2846-2846 ◽  
Author(s):  
Nan-Nan Zhang ◽  
Lei Chen ◽  
Wu Zhang ◽  
Xian-Yang Li ◽  
Lin-Jia Jiang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Mrna Levels ◽  
Terminal Part ◽  
Granulocytic Differentiation ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

Abstract Acute promyelocytic leukemia (APL) is initiated by the formation of PML/RARα oncogenic fusion protein, a potent transcriptional repressor. Retinoid acid (RA) at pharmacological dosage can physically bind to the PML/RARα protein, ushering in the unfolding of downstream programs normally regulated by the wild type RARα. However, through what particular regulatory pathways RA inhibits APL malignant hematopoiesis has remained largely obscured. Rig-I is one of the genes whose mRNA levels were highly up-regulated, along with all-trans-RA (ATRA)-induced terminal granulocytic differentiation of APL cell line NB4 cells in vitro. Based on the analysis of a Rig-I−/− mouse model, recently we have reported a critical regulatory role of Rig-I in normal granulopoiesis. To understand the functional contribution of Rig-I induction in RA-mediated leukemia cell differentiation, we converted a pair of previously reported Rig-I RNAi-duplex sequences into a miR30a-based small hairpin-encoding sequence, which was expressed under the CMV enhancer/promoter within a lentiviral vector. As expected, Rig-I shRNAmir30 infection induced a significant knockdown of Rig-I protein level, and accordingly its delivery into HL-60 cells partially inhibited ATRA-induced granulocytic differentiation, growth inhibition/cell cycle arrest and apoptosis induction, suggesting that Rig-I upregulation participates in RA-induced granulocytic differentiation of acute myeloid leukemia cells. In order to investigate the effect of Rig-I induction on the proliferation of APL cells in vivo, we transduced PML/RARα-harboring leukemic cells with vector or Rig-I-expressing retrovirus, and then transplanted these cells into the syngeneic mice. The vector-transduced APL cells readily expanded in vivo, but the proliferation of Rig-I-transduced cells was apparently prohibited. Moreover, we found that the forced expression of Rig-I induced the expression of numerous ISGs in APL cells, which was recapitulated by the transduction of the C terminal part of Rig-I, but not by the N terminal part. In line with this, during the in vitro short-term culture post-IFNγ or IFNα stimulation, Stat1 phosphorylation at p701 in Rig-I−/− granulocytes was significantly inhibited. In parallel, the induction of multiple ISGs by IFNs was also significantly impaired. In conclusion, our findings indicate that the Rig-I induction inhibited APL reconstitution potentially through up-regulating a number of ISGs via regulating Stat1Tyr701 phosphorylation.

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