Role of JWA in acute promyelocytic leukemia cell differen- tiation and apoptosis triggered by retinoic acid, 12-tet- radecanoylphorbol-13-acetate and arsenic trioxide

2002 ◽  
Vol 47 (10) ◽  
pp. 834 ◽  
Author(s):  
Haixia CAO
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Acute Promyelocytic Leukemia Cell

Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk

Blood ◽  
2002 ◽  
Vol 99 (3) ◽  
pp. 1014-1022 ◽  
Author(s):  
Qi Zhu ◽  
Ji-Wang Zhang ◽  
Hai-Qing Zhu ◽  
Yu-Lei Shen ◽  
Maria Flexor ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Cross Talk ◽  
Fusion Gene ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Dependent Manner ◽  
Induced Differentiation

Abstract Acute promyelocytic leukemia (APL) is characterized by the specific chromosome translocation t(15;17) with promyelocytic leukemia-retinoic acid receptor-α (PML-RARA) fusion gene and the ability to undergo terminal differentiation as an effect of all-trans retinoic acid (ATRA). Recently, arsenic trioxide (As2O3) has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. At the cellular level, As2O3 triggers apoptosis and a partial differentiation of APL cells in a dose-dependent manner; both effects are observed in vivo among patients with APL and APL animal models. To further explore the mechanism of As2O3-induced differentiation, the combined effects of arsenic and a number of other differentiation inducers on APL cell lines (NB4 and NB4-R1) and some fresh APL cells were examined. The data show that a strong synergy exists between a low concentration of As2O3 (0.25 μM) and the cyclic adenosine monophosphate (cAMP) analogue, 8-CPT-cAMP, in fully inducing differentiation of NB4, NB4-R1, and fresh APL cells. Furthermore, cAMP facilitated the degradation of As2O3-mediated fusion protein PML-RARα, a process considered to play a key role in overcoming the differentiation arrest of APL cells. On the other hand, cAMP could significantly inhibit cell growth by modulating several major players in G1/S transition regulation. Interestingly, H89, an antagonist of protein kinase A, could block the differentiation-inducing effect of As2O3potentiated by cAMP. These results thus support the existence of a novel signaling cross-talk for APL maturation, which may deepen understanding of As2O3-induced differentiation in vivo, and thus furnish insights for new therapeutic strategies.

Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1133-1140 ◽  
Author(s):  
Christian Kardinal ◽  
Marc Dangers ◽  
Angelika Kardinal ◽  
Alexandra Koch ◽  
Dominique Tobias Brandt ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Cell Line ◽  
Tyrosine Phosphorylation ◽  
Acute Promyelocytic Leukemia ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Leukemia Cell Line ◽  
Acute Promyelocytic Leukemia Cell ◽  
Promyelocytic Leukemia Cell Line

AbstractWe have investigated the role of tyrosine phosphorylation of the cyclin-dependent kinase (cdk) inhibitor p27Kip1 using the acute promyelocytic leukemia cell line NB4 together with granulocyte colony-stimulating factor (G-CSF). Short-term G-CSF stimulation resulted in a rapid tyrosine dephosphorylation of p27Kip1 accompanied by a change in its binding preferences to cdks. On G-CSF stimulation, p27Kip1 dissociated from cdk4 and associated with cdk2. Binding assays with recombinant p27Kip1 confirmed that tyrosine-phosphorylated p27Kip1 preferentially bound to cdk4, whereas unphosphorylated protein preferentially associated with cdk2. In addition, studies with p27Kip1 point mutations revealed a decisive role of Tyr88 and Tyr89 in binding to cdk4. Furthermore, phosphorylation of Tyr88 and Tyr89 was accompanied by strong nuclear translocation of p27Kip1. Taken together, this report provides the first evidence that tyrosine phosphorylation of p27Kip1 plays a crucial role in binding to cdks and its subcellular localization. Moreover, both effects are mediated by application of G-CSF.

Src Family Kinase Inhibitor PP2 Enhances Differentiation Of Acute Promyelocytic Leukemia Cell Line Induced By Combination Of ATRA and Arsenic Trioxide

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4911-4911
Author(s):  
Kyoung Ha Kim ◽  
Hee-Jeong Cheong ◽  
Sook-Ja Kim ◽  
Jina Yoon ◽  
Han Jo Kim ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Kinase Inhibitor ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Leukemia Cell Line ◽  
Similar Data ◽  
Src Family Kinase ◽  
Nb4 Cells

Abstract All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is an alternative for patients who cannot tolerate anthracycline therapy. We demonstrated that SFK (Src Family Kinase) inhibitor PP2 enhanced acute promyelocytic leukemia (APL) cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated SFK inhibitor PP2 could enhances the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene. Treatment of NB4 cells with 1 nM of ATRA, 0.5 uM of ATO, or 10 uM of PP2 for 72 hours induced expression of CD11b-positive cells by 13.01%, 11.53% or 13.28%, respectively. However, the combination of ATRA and ATO and the combination of three agents (ATRA, ATO, and PP2) led to a significant higher expression of CD11b-positive cells (30.96% and 63.17%, respectively). The synergistic effect of the combination of three agents was more significant than the combination of ATRA and ATO. These results were confirmed by NBT staining. These effects were not related with apoptosis. Annexin-V-fluorescene staining revealed that combination of ATRA and ATO and combination of three agents did not induced apoptosis in NB4 cells. The expression of ICAM-1 was markedly increased in cells treated with the combination of three agents. These findings suggest that the SFK inhibitor can enhances differentiation of APL cells combined with ATRA and ATO. FDA approved SFK inhibitors, such as dasatinib and bosutinib, may be beneficial for the treatment of APL in combination with ATRA and ATO. Disclosures: No relevant conflicts of interest to declare.

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