JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia

Warsch, Wolfgang; Walz, Christoph; Sexl, Veronika

doi:10.1182/blood-2013-02-485573

Cited by 87 publications

(73 citation statements)

References 102 publications

(121 reference statements)

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“…Similar findings were found in human renal cell carcinomas with down-regulated EpoR (Wu et al, 2012). However, the expression of JAK2 and STAT5 remained unchanged, suggesting that Rg1 might induce fusion protein like BCR-ABL1 degradation to suppress the constitutive activation of JAK2 and STAT5 (Warsch et al, 2013).…”

Section: Discussionsupporting

confidence: 79%

Ginsenoside Rg1 Induces Apoptosis through Inhibition of the EpoR-Mediated JAK2/STAT5 Signalling Pathway in the TF-1/Epo Human Leukemia Cell Line

Li¹,

Wei²,

Zuo³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Ginsenoside Rg1 is one effective anticancer and antioxidant constituent of total saponins of Panax ginseng (TSPG), which has been shown to have various pharmacological effects. Our previous study demonstrated that Rg1 had anti-tumor activity in K562 leukemia cells. The aim of this study was designed to investigate whether Rg1 could induce apoptosis in TF-1/Epo cells and further to explore the underlying molecular mechanisms. Here we found that Rg1 could inhibit TF-1/Epo cell proliferation and induce cell apoptosis in vitro in a concentration and time dependent manner. It also suppressed the expression of EpoR on the surface membrane and inhibited JAK2/STAT5 pathway activity. Rg1 induced up-regulation of Bax, cleaved caspase-3 and C-PAPR protein and down-regulation of Bcl-2 and AG490, a JAK2 specific inhibitor, could enhance the effects of Rg1. Our studies showed that EpoR-mediated JAK2/STAT5 signaling played a key role in Rg1-induced apoptosis in TF-1/Epo cells. These results may provide new insights of Rg1 protective roles in the prevention and treatment of leukemia.

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Section: Discussionsupporting

confidence: 79%

Ginsenoside Rg1 Induces Apoptosis through Inhibition of the EpoR-Mediated JAK2/STAT5 Signalling Pathway in the TF-1/Epo Human Leukemia Cell Line

Li¹,

Wei²,

Zuo³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…This paradigm is likely the result of the fact that pharmacological agents labeled "JAK2 inhibitors" were being utilized in most of the recently published experiments. However, these drugs are known to block several JAKs, sometimes with identical efficacies (50). A striking argument against the role of JAK2 as the master regulator of STAT3 comes from the analysis of our JAK2 conditional knockout model.…”

Section: Discussionmentioning

confidence: 99%

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Sakamoto

Wehde

Yoo

et al. 2016

Molecular and Cellular Biology

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Despite a wealth of knowledge about the significance of individual signal transducers and activators of transcription (STATs), essential functions of their upstream Janus kinases (JAKs) during postnatal development are less well defined. Using a novel mammary gland-specific JAK1 knockout model, we demonstrate here that this tyrosine kinase is essential for the activation of STAT1, STAT3, and STAT6 in the mammary epithelium. The loss of JAK1 uncouples interleukin-6-class ligands from their downstream effector, STAT3, which leads to the decreased expression of STAT3 target genes that are associated with the acutephase response, inflammation, and wound healing. Consequently, JAK1-deficient mice exhibit impaired apoptosis and a significant delay in mammary gland remodeling. Using RNA sequencing, we identified several new JAK1 target genes that are upregulated during involution. These include Bmf and Bim, which are known regulators of programmed cell death. Using a BMF/BIMdouble-knockout epithelial transplant model, we further validated that the synergistic action of these proapoptotic JAK1 targets is obligatory for the remodeling of the mammary epithelium. The collective results of this study suggest that JAK1 has nonredundant roles in the activation of particular STAT proteins and this tyrosine kinase is essential for coupling inflammatory cytokine signals to the cell death machinery in the differentiated mammary epithelium.T he postnatal growth, functional differentiation, and postlactational remodeling of the epithelial compartment of the mammary gland are controlled by hormones and locally synthesized cytokines (1). While estrogen is primarily required for the elongation of mammary ducts after the onset of puberty (2, 3), progesterone and prolactin orchestrate the specification, proliferation, and differentiation of secretory alveolar cells during pregnancy (4-6). Following lactation and the weaning of the young, circulating levels of prolactin (PRL) decline and milk stasis induces the local production of interleukin-6 (IL-6)-class cytokines, in particular, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM). These IL-6-class cytokines trigger a cascade of intracellular events that orchestrate a process known as mammary gland remodeling, which entails the death and selective removal of terminally differentiated alveolar cells (7-9).PRL and IL-6-class cytokines signal through their corresponding receptors and utilize Janus kinases (JAKs) to activate downstream signal transducers and activators of transcription (STATs) that subsequently alter the transcriptional profile, growth, and homeostasis of mammary epithelial cells. Five of the seven STAT proteins that are known in mammals (i.e., STAT1, STAT3, STAT5a, STAT5b, and STAT6) have been found to be sequentially activated at defined stages of mammary gland development (10, 11). The levels of phosphorylated STAT1 have been reported to be elevated in nulliparous females, but this particular transcription factor seems to be largely dispensable for normal ma...

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“…[80][81][82][83] Because of the factors outlined here, there is a compelling argument for conducting trials in children and adolescents to study combinations of TKIs with other agents such as JAK2 inhibitors 83,84 and interferon-a 85,86 that do affect leukemic stem cells. With the goal of avoiding lifelong TKI treatment, strategies that permanently eliminate the CML clone-for example, using limited duration, more intensive chemotherapy in combination with TKIs, similar to approaches used in recent trials of Ph 1 ALL…”

Section: Pediatric CML May Require a Different Approach To Tki Treatmentmentioning

confidence: 99%

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach

Hijiya

Schultz

Metzler

et al. 2016

Blood

155

176

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Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.

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JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia

Cited by 87 publications

References 102 publications

Ginsenoside Rg1 Induces Apoptosis through Inhibition of the EpoR-Mediated JAK2/STAT5 Signalling Pathway in the TF-1/Epo Human Leukemia Cell Line

Ginsenoside Rg1 Induces Apoptosis through Inhibition of the EpoR-Mediated JAK2/STAT5 Signalling Pathway in the TF-1/Epo Human Leukemia Cell Line

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach

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