IL-21 Contributes to JAK3/STAT3 Activation and Promotes Cell Growth in ALK-Positive Anaplastic Large Cell Lymphoma

Bard, Jennifer Dien; Gélébart, Pascal; Anand, Mona; Zak, Zoulika; Hegazy, Samar; Amin, Hesham M.; Lai, Raymond

doi:10.2353/ajpath.2009.080982

Cited by 52 publications

(21 citation statements)

References 48 publications

(53 reference statements)

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“…7, 19, 20 Inhibition of STAT3 and its signaling prevents SMC proliferation and injury-induced neointimal formation. 16, 19 JNK has also been shown to mediate PDGF-BB-induced SMC proliferation and injury-induced neointima formation. 16, 22 Therefore, we hypothesized that JAK3 may regulate PDGF-BB-mediated SMC proliferation by activating STAT3 and/or JNK signaling.…”

Section: Resultsmentioning

confidence: 99%

Janus Kinase 3, a Novel Regulator for Smooth Muscle Proliferation and Vascular Remodeling

Wang

Cui

Chuang

et al. 2017

ATVB

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Objective Vascular remodeling due to smooth muscle cell (SMC) proliferation is a common process occurring in a number of vascular diseases such as atherosclerosis, aortic aneurysm, post-transplant vasculopathy, and restenosis after angioplasty, etc. The molecular mechanism underlying SMC proliferation, however, is not completed understood. The objective of this study is to determine the role and mechanism of Janus kinase 3 (JAK3) in vascular remodeling and SMC proliferation. Approach and Results Platelet-derived growth factor (PDGF)-BB, a SMC mitogen, induces JAK3 expression and phosphorylation while stimulating SMC proliferation. Janex-1, a specific inhibitor of JAK3, or knockdown of JAK3 by shRNA, inhibits the SMC proliferation. Conversely, ectopic expression of JAK3 promotes SMC proliferation. Mechanistically, JAK3 promotes the phosphorylation of signal transducer and activator of transcription 3 and c-Jun N-terminal kinase in SMC, two signaling pathways known to be critical for SMC proliferation and vascular remodeling. Blockade of these two signaling pathways by their inhibitors impeded the JAK3-mediated SMC proliferation. In vivo, knockdown of JAK3 attenuates injury-induced neointima formation with attenuated neointimal SMC proliferation. Knockdown of JAK3 also induces neointimal SMC apoptosis in rat carotid artery balloon-injury model. Conclusion Our results demonstrate that JAK3 mediates SMC proliferation and survival during injury-induced vascular remodeling, which provides a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

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Section: Resultsmentioning

confidence: 99%

Janus Kinase 3, a Novel Regulator for Smooth Muscle Proliferation and Vascular Remodeling

Wang

Cui

Chuang

et al. 2017

ATVB

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“…Because of the described role of miR‐155 in the immune system, we assumed that miR‐155 might modulate the tumour environment via cytokines . Therefore, we assessed the effect of miR‐155 over‐expression on the expression and secretion of a cytokine subset (IL‐8, IL‐10, IL‐21 and IL‐22) described in ALCL . When Karpas‐299 and SR786 cells were transduced with pre‐miR‐155, IL‐8 transcript levels were reduced by 80% in both cell lines (Figure A).…”

Section: Resultsmentioning

confidence: 99%

Oncogenic role of miR‐155 in anaplastic large cell lymphoma lacking the t(2;5) translocation

Merkel

Hamacher

Griessl

et al. 2015

The Journal of Pathology

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Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM–ALK) fusion protein (ALCL ALK+). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK−), which is characterized by a worse prognosis. We found that ALCL ALK−, in contrast to ALCL ALK+, lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK+ cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK−, we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK− and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Except in the context of ALCL, in which the NPM-ALK fusion protein was reported to physically interact with and activate JAK3 (Crockett et al, 2004), the mechanistic basis for constitutive JAK3 activation, as well as its precise contribution to other lymphoid disorders, is unclear. Of note, inhibition of JAK3 appears important for the growth of NPM-ALK + lymphoma celIs in vitro (Amin et al, 2003; Dien Bard et al, 2009). In addition, a pan-JAK inhibitor efficiently inhibited the proliferative phenotype of isolated murine CD8 + T cells expressing JAK3A572 V in vitro (Cornejo et al, 2009).…”

Section: Therapeutic Use Of Jak3 Inhibitorsmentioning

confidence: 99%

JAK3: A two-faced player in hematological disorders

Cornejo¹,

Boggon²,

Mercher³

2009

The International Journal of Biochemistry & Cell Biology

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JAK3 is a non-receptor tyrosine kinase, predominantly expressed in hematopoietic cells and that has been implicated in the signal transduction of the common gamma chain subfamily of cytokine receptors. As a result, JAK3 plays an essential role in hematopoieisis during T cell development. JAK3 inactivating mutations result in immunodeficiency syndromes (SCID) in both humans and mice. Recent data indicate that abnormal activation of JAK3 due to activating mutations is also found in human hematological malignancies, including acute megakaryoblastic leukemia (AMKL) and cutaneous T celI lymphoma (CTCL). After a brief summary of the JAK3 structure and function, we will review the evidence on the emerging role of JAK3 activation in hematological malignancies that warrant further studies to test the relevance of specific inhibition of JAK3 as a therapeutic approach to these challenging clinical entities.

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IL-21 Contributes to JAK3/STAT3 Activation and Promotes Cell Growth in ALK-Positive Anaplastic Large Cell Lymphoma

Abstract: Interleukin (IL)-

Cited by 52 publications

References 48 publications

Janus Kinase 3, a Novel Regulator for Smooth Muscle Proliferation and Vascular Remodeling

Janus Kinase 3, a Novel Regulator for Smooth Muscle Proliferation and Vascular Remodeling

Oncogenic role of miR‐155 in anaplastic large cell lymphoma lacking the t(2;5) translocation

JAK3: A two-faced player in hematological disorders

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