Expression and significance of Pim‐3 kinase in adult T‐cell leukemia

Ishikawa, Chie; Senba, Masachika; Hashimoto, Tadashi; Imaizumi, Atsushi; Mori, Nozomu

doi:10.1111/ejh.12940

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…The expression of PIM2 kinase was found to be higher in MM than in any other cancer type[14]. Recent research showed that inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma[15] and that targeting PIM3 may have activity against adult T-cell leukemia[16]. It has also been reported that PIM1 mRNA expression is a potential prognostic biomarker in acute myeloid leukemia[17].…”

Section: Introductionmentioning

confidence: 99%

Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade

et al. 2019

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Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan-PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma.

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Section: Introductionmentioning

confidence: 99%

Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade

et al. 2019

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“…Very few previous studies have evaluated the expression and function of PIM3 in AML. 21,22 Here, we revealed a high level of PIM3 expression in AML cells relative to healthy donor PBMCs. Moreover, we observed distinctive expression patterns of PIM1, PIM2, and PIM3 in AML, 10,11,13,22 and our results suggest that PIM3 expression is subject to regulation via a unique upstream process.…”

Section: Discussionmentioning

confidence: 74%

“…However, the expression and function of PIM3 in leukemia are relatively less understood. Previously, Ishikawa et al observed that PIM3 knockdown suppressed cell growth in T cell leukemia cell lines, 21 whereas Zhou et al compared PIM3 expression in AML patients before and after chemotherapy and observed that changes in this parameter during the treatment correlated with the patient’s remission status. 22 In this study, we performed both clinical data analyses and cell line studies to further elucidate the function of PIM3 in AML, and observed regulatory effects on proliferation, survival and chemotaxis.…”

Section: Introductionmentioning

confidence: 99%

<p>PIM3 Promotes the Proliferation and Migration of Acute Myeloid Leukemia Cells</p>

Luo

Sun

Zheng

et al. 2020

OTT

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Purpose Acute myeloid leukemia (AML) is associated with a poor overall prognosis. PIM family genes, including PIM1, PIM2 , and PIM3 , are proto-oncogenes that are aberrantly overexpressed in different types of human cancers. In this study, we aimed to explore and clarify the function of PIM3 in AML. Patients and Methods The expression of the three PIM genes in AML was detected using the Gene Expression Omnibus. The expression of PIM3 and PIM3 in patient samples and AML cell lines was measured using quantitative real-time polymerase chain reaction or Western blot analyses. The cellular behaviors of PIM3 -overexpressing AML cell lines were detected using a CCK-8 assay, flow cytometry, Western blotting, immunofluorescence staining, and a cell migration assay. The interactions between PIM3 and phosphorylated CXCR4 (pCXCR4) were explored via immunoprecipitation. Results Higher PIM3 expression was detected in primary AML cells than in healthy donor cells. Second, PIM3 overexpression promoted AML cell proliferation and protected against spontaneous apoptosis by phosphorylating BAD (pBAD) at Ser112. Furthermore, PIM3 overexpression might promote the migration of AML cells via CXCR4. PIM3 -overexpressing AML cell lines exhibited increased CXCR4 phosphorylation at Ser339, and pCXCR4 interacted with PIM3. Conclusion Our findings suggest that PIM3 regulates the proliferation, survival, and chemotaxis of AML cell lines. Moreover, pCXCR4 might mediate the regulation of PIM3-induced chemotaxis. Therefore, the inhibition of PIM3 expression may be a promising therapeutic target in AML.

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“…On the other hand, MT2A helps regulate NF-kB activity by modulating expression of IkB-a and has been shown to play a role in transmitting inflammatory signals to the vascular endothelium [54,55]. PIM3, which encodes a serine/threonine kinase, is one of several regulatory kinases that can be induced by NF-kB, which functions upstream of IkB-a and can lead to further activation of NF-kB itself (canonical) [56,57]. These findings suggest a complex cellular environment within the lumen of unruptured IAs, in which inflammatory pathways, potentially activated by MCP-1, RANTES, MIG, Eotaxin, IL-8, and IL-17, are regulated through NF-kB mediated transcription and downstream signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

Tutino

Ishii

et al. 2021

Diagnostics

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The rupture of an intracranial aneurysm (IA) causes devastating hemorrhagic strokes. Yet, most IAs remain asymptomatic and undetected until they rupture. In the search for circulating biomarkers of unruptured IAs, we previously performed transcriptome profiling on whole blood and identified an IA-associated panel of 18 genes. In this study, we seek to determine if these genes are also differentially expressed within the IA lumen, which could provide a mechanistic link between the disease and the observed circulating gene expression patterns. To this end, we collected blood from the lumen of 37 IAs and their proximal parent vessels in 31 patients. The expression levels of 18 genes in the lumen and proximal vessel were then measured by quantitative polymerase chain reaction. This analysis revealed that the expression of 6/18 genes (CBWD6, MT2A, MZT2B, PIM3, SLC37A3, and TNFRSF4) was significantly higher in intraluminal blood, while the expression of 3/18 genes (ST6GALNAC1, TCN2, and UFSP1) was significantly lower. There was a significant, positive correlation between intraluminal and proximal expression of CXCL10, MT2A, and MZT2B, suggesting local increases of these genes is reflected in the periphery. Expression of ST6GALNAC1 and TIFAB was significantly positively correlated with IA size, while expression of CCDC85B was significantly positively correlated with IA enhancement on post-contrast MRI, a metric of IA instability and risk. In conclusion, intraluminal expression differences in half of the IA-associated genes observed in this study provide evidence for IA tissue-mediated transcriptional changes in whole blood. Additionally, some genes may be informative in assessing IA risk, as their intraluminal expression was correlated to IA size and aneurysmal wall enhancement.

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Expression and significance of Pim‐3 kinase in adult T‐cell leukemia

Abstract: Pim-3 is a potentially suitable target for the development of novel therapeutic agents against ATL.

Cited by 5 publications

References 47 publications

Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade

Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade

<p>PIM3 Promotes the Proliferation and Migration of Acute Myeloid Leukemia Cells</p>

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

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