scholarly journals Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis

Cancer Cell ◽  
2020 ◽  
Vol 37 (2) ◽  
pp. 200-215.e5 ◽  
Author(s):  
Jue Jiang ◽  
Jingchao Wang ◽  
Ming Yue ◽  
Xiaolian Cai ◽  
Tianci Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Aurora B ◽  
Aurora B Kinase ◽  
T Cell Leukemogenesis

Analysis of Aurora B Kinase in Non-Hodgkin’s Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1610-1610
Author(s):  
Takayuki Ikezoe ◽  
Tamotsu Takeuchi ◽  
Chie Nishioka ◽  
Yoshihiro Adachi ◽  
Mutsuo Furihata ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Molecular Target ◽  
Hodgkin's Lymphoma ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Non Hodgkin's Lymphoma

Abstract Aurora B kinase is one of the key regulators of mitosis and has been reported to be over-expressed in a various malignancies including acute myelogenous leukemia; however, expression of Aurora B in non-Hodgkin’s lymphoma (NHL) and its role in lymphoma genesis remain to be fully elucidated. This study explored the levels of Aurora B in seventy four lymph nodes and tumor specimens excised operatively from individuals with various types of NHLs including diffuse large B cell lymphoma (n=22, DLBCL), follicular lymphoma (n=12, FL), Burkitt’s lymphoma (n=10, BL), mantle cell lymphoma (n=4, MCL), mucosa associated lymphoid tissue (n=4, MALT), adult T-cell leukemia/lymphoma (n=11, ATL), peripheral T-cell lymphoma (n=8, PTCL), and Hodgkin’s lymphoma (n=3, HL). Immunohistochemical examination found that DLBCL (11/22, 50 %) and BL (8/10, 80 %) cells highly (percentage of positive cells, >20 %) expressed Aurora B in their nucleus. On the other hand, FL (11/12, 92 %), MCL (1/4, 25 %), and MALT (1/4, 25 %) cells slightly (percentage of positive cells, 5–20 %) expressed Aurora B and none of them, except for one case of FL, highly expressed this protein kinase, suggesting that expression of Aurora B correlated with histological grade in B cell NHLs (p=0.0004). We next examined whether Aurora B could be a molecular target for treatment of NHLs utilizing BALM-14, -18, and -27, Daudi, Ramos, and Raji Burkitt’s lymphoma/leukemia cells. Exposure of these cells to AZD1152, a selective inhibitor of Aurora B kinase, potently induced apoptosis in association with activation of caspase 3, as measured by annexin V staining and Western blot analysis, respectively. Moreover, we found that AZD1152 synergistically enhanced the effects of vincristine (VCR), a tubulin depolymerizing agent, to induce growth arrest and apoptosis of these cells. Further experiments found that VCR increased levels of the phosphorylated forms of Aurora B (p-Aurora B) via activation of c-Jun N-terminal kinase (JNK), which was blocked in the presence of AZD1152 in BALM-27 cells. Taken together, Aurora B kinase is a promising molecular target for treatment of individuals with aggressive types of NHLs. The combined administration of AZD1152 and the conventional chemotherapeutic agents to patients with NHL warrants further investigation.

scholarly journals Phase II Intergroup Trial of Alisertib in Relapsed and Refractory Peripheral T-Cell Lymphoma and Transformed Mycosis Fungoides: SWOG 1108

2015 ◽  
Vol 33 (21) ◽  
pp. 2399-2404 ◽  
Author(s):  
Paul M. Barr ◽  
Hongli Li ◽  
Catherine Spier ◽  
Daruka Mahadevan ◽  
Michael LeBlanc ◽  
...  
Keyword(s):  
T Cell ◽  
Mycosis Fungoides ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Phase Iii ◽  
Aurora B ◽  
Aurora A Kinase ◽  
Aurora B Kinase

Purpose Aurora A kinase (AAK) is upregulated in highly proliferative lymphomas, suggesting its potential as a therapeutic target. Alisertib is a novel oral AAK inhibitor without adverse safety signals in early-phase studies that demonstrated preliminary activity in T-cell lymphoma. This phase II study was conducted to further investigate the efficacy of alisertib in relapsed or refractory peripheral T-cell non-Hodgkin lymphoma (PTCL). Patients and Methods Eligible patients with histologically confirmed relapsed/refractory PTCL or transformed Mycosis fungoides (tMF) received alisertib 50 mg twice a day for 7 days on 21-day cycles. Results Of 37 eligible patients, the histologic subtypes enrolled included PTCL not otherwise specified (n = 13), angioimmunoblastic T-cell lymphoma (n = 9), tMF (n = 7), adult T-cell lymphoma/leukemia (n = 4), anaplastic large-cell lymphoma (n = 2), and extranodal natural killer/T-cell lymphoma (n = 2). Grade 3 and 4 adverse events in ≥ 5% of patients included neutropenia (32%), anemia (30%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%), and rash (5%). Treatment was discontinued most commonly for disease progression. Among the PTCL subtypes, the overall response rate was 30%, whereas no responses were observed in tMF. Aurora B kinase was more commonly overexpressed than AAK in tumor specimens. Analysis of AAK, Aurora B kinase, MYC, BCL-2, phosphatidylinositol 3-kinase γ, and Notch1 expression revealed no association with response. Conclusion Alisertib has antitumor activity in PTCL, including heavily pretreated patients. These promising results are being further investigated in an ongoing international, randomized phase III trial comparing alisertib with investigator's choice in PTCL.

Direct Phosphorylation and Stabilization of MYC By Aurora B Kinase Promotes T Cell Leukemogenesis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 732-732
Author(s):  
Hudan Liu ◽  
Jue Jiang ◽  
Jingchao Wang ◽  
Ming Yue ◽  
Hui Feng ◽  
...  
Keyword(s):  
Cell Division ◽  
T Cell ◽  
Time Course ◽  
Lymphoblastic Leukemia ◽  
Fluorescent Microscopy ◽  
Biological Significance ◽  
Aurora B ◽  
Aurora Kinases ◽  
T Cell Leukemogenesis

The aberrant activation of oncogene MYC (also termed c-MYC) is one of the most common features in human cancer. The unleashed MYC oncogene frequently produces abundant MYC protein, which mediates a transcriptional response involved in a variety of biological processes, contributing to almost every aspect of tumorigenesis. The significance of MYC deregulation has been recognized in T-cell acute lymphoblastic leukemia (T-ALL), a life-threatening hematological malignancy with dismal outcome due to disease relapse and drug resistance. Therapeutic efforts aimed at inhibiting MYC expression or activity should have an important clinical relevance. However, attempts to directly disrupt MYC function have met with limited success, in part due to its "undruggable" protein structure. Aurora kinases, a multi-genic family of serine/threonine kinases, consist Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC). They are known to play an integral role in the regulation of cell division and chromosomal segregation. Amplification or overexpression of Aurora kinases is frequently found in human cancers with clear evidence of oncogenic potential, implicating Aurora kinases as rational anti-tumor targets. AURKB is the catalytic subunit of the chromosomal passenger protein complex (CPPC) which regulates multiple facets of cell division. Overexpression of AURKB has been reported in a variety of cancers and predicts poor overall survival. AZD1152 is a highly potent and selective inhibitor of Aurora B; preclinical evidence of anti-tumor efficacy with AZD1152 has extended to the clinical setting with tolerable toxicity. Despite considerable study, it remains largely unclear how expression of AURKB is elevated and, in particular, how elevated levels of AURKB reprogram cells to promote the cancer progression. We identified AURKB as a novel MYC binding partner using liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. To assess the potential role of AURKB in regulating MYC, we inhibited AURKB in multiple T-ALL cell lines and found that MYC protein expression was diminished significantly. Notably, depletion of AURKB failed to downregulate MYC mRNA, suggesting a post-transcriptional regulation of the MYC protein. We then assessed MYC protein decay in the presence or absence of AURKB expression. Time course experiments revealed that knockdown of AURKB significantly shortened the half-life of endogenous MYC in T-ALL cells. Consistently, AURKB depletion resulted in significant downregulation of MYC-induced gene expression programs, corroborating an essential role of AURKB in sustaining MYC transcriptional activities. Regulation of MYC degradation by ubiquitin-proteasome system is dependent on MYC phosphorylation. Initiation of MYC turnover requires GSK3b-mediated phosphorylation of threonine 58 (p-T58). Time-course analysis showed that treatment with AZD1152 in T-ALL cells resulted in a notable increase in MYC p-T58. We performed in vitro kinase assays and found that MYC is phosphorylated directly by AURKB. This phosphorylation counteracted GSK3b-directed Thr58 phosphorylation and subsequent FBW7-mediated proteasomal degradation and enhanced the MYC protein stability. The AURKB mRNA and protein are generally more abundant in human T-ALL than normal thymocytes. We demonstrated that MYC, in concert with TAL1, directly binds to the AURKB promoter and activates its transcription, thus constituting a reciprocal regulation between MYC and AURKB. In order to clarify the biological significance of the AURKB-MYC circuit, we co-injected the one-cell-stage zebrafish embryos with the rag2:EGFP-Myc construct alone or together with rag2:AURKB followed by fluorescent microscopy analysis. Our results demonstrate that AURKB phosphorylation of MYC is functionally important for T cell leukemogenesis in vivo. Moreover, inhibition of AURKB elicits dramatic MYC degradation in association with robust apoptosis in wild type-FBW7 T-ALL cells, suggesting that FBW7 mutational status may serve as a genetic predictor of sensitivity to AURKB inhibitors. In this study, we unravel a non-mitotic role of AURKB in promoting MYC stabilization via direct MYC phosphorylation at an unconventional site. Our findings decipher a previously unsuspected mechanism involved in MYC deregulation and highlight disruption of the AURKB-MYC signaling circuit as a promising T-ALL therapeutic strategy. Disclosures No relevant conflicts of interest to declare.

scholarly journals A complex containing the Sm protein CAR-1 and the RNA helicase CGH-1 is required for embryonic cytokinesis in Caenorhabditis elegans

2005 ◽  
Vol 171 (2) ◽  
pp. 267-279 ◽  
Author(s):  
Anjon Audhya ◽  
Francie Hyndman ◽  
Ian X. McLeod ◽  
Amy S. Maddox ◽  
John R. Yates ◽  
...  
Keyword(s):  
Cell Division ◽  
Caenorhabditis Elegans ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Rna Helicase ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Daughter Cells ◽  
Sm Protein ◽  
Spindle Structure

Cytokinesis completes cell division and partitions the contents of one cell to the two daughter cells. Here we characterize CAR-1, a predicted RNA binding protein that is implicated in cytokinesis. CAR-1 localizes to germline-specific RNA-containing particles and copurifies with the essential RNA helicase, CGH-1, in an RNA-dependent fashion. The atypical Sm domain of CAR-1, which directly binds RNA, is dispensable for CAR-1 localization, but is critical for its function. Inhibition of CAR-1 by RNA-mediated depletion or mutation results in a specific defect in embryonic cytokinesis. This cytokinesis failure likely results from an anaphase spindle defect in which interzonal microtubule bundles that recruit Aurora B kinase and the kinesin, ZEN-4, fail to form between the separating chromosomes. Depletion of CGH-1 results in sterility, but partially depleted worms produce embryos that exhibit the CAR-1–depletion phenotype. Cumulatively, our results suggest that CAR-1 functions with CGH-1 to regulate a specific set of maternally loaded RNAs that is required for anaphase spindle structure and cytokinesis.

scholarly journals Aurora B kinase activation requires survivin priming phosphorylation by PLK1

2010 ◽  
Vol 3 (4) ◽  
pp. 260-267 ◽  
Author(s):  
Youjun Chu ◽  
Phil Y. Yao ◽  
Wenwen Wang ◽  
Dongmei Wang ◽  
Zhikai Wang ◽  
...  
Keyword(s):  
Aurora B ◽  
Aurora B Kinase ◽  
Kinase Activation
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