The use of arsenic-containing compounds in the treatment of leukemias and other malignancies dates several decades back in time (1). Despite the known existence of arsenic compounds for hundreds of years, only recently has a derivative of this heavy metal, arsenic trioxide (As 2 O 3 ), found an established role in the treatment of a human disease. Extensive work has now established that As 2 O 3 exhibits potent pro-apoptotic effects against malignant cells and has important antineoplastic activities in vitro and in vivo (2-6). Importantly, As 2 O 3 has been approved for the treatment of acute promyelocytic leukemia (APL) 2 in humans, and its introduction in the therapy of this form of acute leukemia has had a major impact in medical oncology (1,(7)(8)(9)(10). Notably, APL is a form of leukemia with unusual sensitivity to the effects of arsenic trioxide. It is well established that induction of differentiation of APL cells occurs at low concentrations (0.5 M), whereas higher (Ն2 M) concentrations are required for the generation of its pro-apoptotic effects in other cell types (2-6). As 2 O 3 is also currently under investigation for the treatment of other hematological malignancies and clonal disorders, including chronic myelogenous leukemia, multiple myeloma, and myelodysplastic syndromes (2, 4, 11-13). A remaining challenge in introducing arsenic trioxide in the treatment of other malignancies is the development of means to enhance arsenic-dependent apoptosis at lower final concentrations. Thus, identification of cellular pathways that could be targeted to enhance the antineoplastic properties of As 2 O 3 are of high translational potential and interest.Previous work has suggested that the pro-apoptotic effects of As 2 O 3 on APL cells correlate with targeting and degradation of the abnormal PML-RAR␣ fusion protein (5, 14, 15), although independent mechanisms also exist (16). Among the genes regulated by the PML-RAR␣ fusion protein is the mitogen-activated protein kinase (MAPK)-interacting kinase 1 (Mnk1) (17, 18), a kinase that was recently shown to be post-translationally stabilized by PML-RAR␣ fusion protein and participate in the control of differentiation of myeloid cells (19). Mnk1 and the related Mnk2 are known to be activated downstream of MAPKs, via phosphorylation at Thr-197 and Thr-202 located in their activation loop (20 -23), and after their activation, they in turn phosphorylate the cap binding eukaryotic initiation factor 4E (eIF4E) at Ser-209 in response to mitogens and stress signals (22,23).In previous work, we had demonstrated that the p38 MAPK is activated in response to treatment of leukemic cells with As 2 O 3 (24) and shown that such activation occurs in a negative feedback regulatory manner, to control and limit arsenic-dependent apoptosis. This was established by studies demonstrating that pharmacological inhibitors of p38 promote generation of As 2 O 3 -dependent apoptosis (24), whereas pro-apoptotic * This work was supported by National Institutes of Health Grants CA121192, CA77816, a...
The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for acute myeloid leukemia (AML). We evaluated the therapeutic potential of the highly-selective MNK1/2 inhibitor Tomivosertib on AML cells. Tomivosertib was highly effective at blocking eIF4E phosphorylation on serine 209 in AML cells. Such inhibitory effects correlated with dose-dependent suppression of cellular viability and leukemic progenitor colony formation. Moreover, combination of Tomivosertib and Venetoclax resulted in synergistic anti-leukemic responses in AML cell lines. Mass spectrometry studies identified novel putative MNK1/2 interactors, while in parallel studies we demonstrated that MNK2 -RAPTOR -mTOR complexes are not disrupted by Tomivosertib. Overall, these findings demonstrate that Tomivosertib exhibits potent anti-leukemic properties on AML cells and support the development of clinical translational efforts involving the use of this drug, alone or in combination with other therapies for the treatment of AML.
Arsenic trioxide (As 2 O 3 ) has potent antileukemic properties in vitro and in vivo, but the mechanisms by which it generates its effects on target leukemic cells are not well understood. Understanding cellular mechanisms and pathways that are activated in leukemic cells to control the generation of As 2 O 3 responses should have important implications in the development of novel approaches using As 2 O 3 for the treatment of leukemias. In this study, we used immunoblotting and immune complex kinase assays to provide evidence that the kinases thousand-and-one amino acid kinase 2 (TAO2) and transforming growth factor--activated kinase 1 (TAK1) are rapidly activated in response to treatment of acute leukemia cells with As 2 O 3 . Such activation occurs after the generation of reactive oxygen species and regulates downstream engagement of the p38 mitogen-activated protein kinase. Our studies demonstrate that siRNA-mediated knockdown of TAO2 or TAK1 or pharmacological inhibition of TAK1 enhances the suppressive effects of As 2 O 3 on KT-1-derived leukemic progenitor colony formation and on primary leukemic progenitors from patients with acute myelogenous leukemia. These results indicate key negative-feedback regulatory roles for these kinases in the generation of the antileukemic effects of As 2 O 3 . Thus, molecular or pharmacological targeting of these kinases may provide a novel approach to enhance the generation of arsenic-dependent antileukemic responses.
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