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

Jiang, Jue; Wang, Jingchao; Ming, Yue; Cai, Xiaolian; Wang, Tianci; Wu, Chao; Su, Hexiu; Wang, Yan‐Wu; Han, Meng; Zhang, Yingchi; Zhu, Xiaofan; Jiang, Peng; Li, Peng; Sun, Yuhan; Xiao, Wuhan; Feng, Hui; Qing, Guoliang; Liu, Hudan

doi:10.1016/j.ccell.2020.01.001

Cited by 66 publications

(40 citation statements)

References 62 publications

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“…Unfortunately, a phase II clinical trial from the Children's Oncology Group reported objective response after alisertib single-agent treatment in less than 5% of the pediatric patients with recurrent/ refractory advanced solid tumor or acute leukemia (139). Recent evidence elucidates a role for AURKB in inhibiting proteasomal degradation of MYC, thus stabilizing this oncogenic protein (140). In vitro treatment of T-ALL cells with the AURKB inhibitor barasertib (AZD1152) leads to reduced MYC protein levels (140) and enhanced cell death (140,141).…”

Section: Other Promising Targeted Treatments In Developmentmentioning

confidence: 99%

“…Recent evidence elucidates a role for AURKB in inhibiting proteasomal degradation of MYC, thus stabilizing this oncogenic protein (140). In vitro treatment of T-ALL cells with the AURKB inhibitor barasertib (AZD1152) leads to reduced MYC protein levels (140) and enhanced cell death (140,141). Furthermore, AZD1152 can act in synergy with vincristine (140).…”

Section: Other Promising Targeted Treatments In Developmentmentioning

confidence: 99%

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T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with TALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent TALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of TALL and gives a comprehensive overview of the novel treatments for patients with TALL that are currently under clinical investigation or that are emerging from preclinical research. Significance: TALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.

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Section: Other Promising Targeted Treatments In Developmentmentioning

confidence: 99%

Section: Other Promising Targeted Treatments In Developmentmentioning

confidence: 99%

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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show abstract

“…1). [10][11][12][13][14][15][16] A large body of evidence demonstrates that enhanced MYC expression is a major driving force of malignant transformation, and that both MYC-driven tumors and tumors driven by other oncogenes (e.g., K-RAS) sustainedly depend on elevated MYC levels for growth. 17,18 The MYC oncoproteins are "super-transcription factors" that potentially regulate the transcription of at least 15% of the entire genome.…”

Section: Introductionmentioning

confidence: 99%

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

Dong

Liu

et al. 2020

Sig Transduct Target Ther

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121

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Cancer cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. As such, most human cancers differ from normal counterpart tissues by a plethora of energetic and metabolic reprogramming. Transcription factors of the MYC family are deregulated in up to 70% of all human cancers through a variety of mechanisms. Oncogenic levels of MYC regulates almost every aspect of cellular metabolism, a recently revisited hallmark of cancer development. Meanwhile, unrestrained growth in response to oncogenic MYC expression creates dependency on MYC-driven metabolic pathways, which in principle provides novel targets for development of effective cancer therapeutics. In the current review, we summarize the significant progress made toward understanding how MYC deregulation fuels metabolic rewiring in malignant transformation.

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“…We assume that this leads to subsequent hampering of GSK3β-dependent phosphorylation, probably by changing the GSK3β recognition domain via the addition of negative charges through the phosphate residues added by IKKα. A similar mechanism was shown for Aurora B kinase (AURKB), which promotes c-Myc stability by phosphorylating serine-67 and counteracting GSK3β-directed threonine 58 phosphorylation [ 45 ].…”

Section: Discussionmentioning

confidence: 74%

The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity

et al. 2021

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Background The IκB kinase (IKK) complex, comprising the two enzymes IKKα and IKKβ, is the main activator of the inflammatory transcription factor NF-κB, which is constitutively active in many cancers. While several connections between NF-κB signaling and the oncogene c-Myc have been shown, functional links between the signaling molecules are still poorly studied. Methods Molecular interactions were shown by co-immunoprecipitation and FRET microscopy. Phosphorylation of c-Myc was shown by kinases assays and its activity by improved reporter gene systems. CRISPR/Cas9-mediated gene knockout and chemical inhibition were used to block IKK activity. The turnover of c-Myc variants was determined by degradation in presence of cycloheximide and by optical pulse-chase experiments.. Immunofluorescence of mouse prostate tissue and bioinformatics of human datasets were applied to correlate IKKα- and c-Myc levels. Cell proliferation was assessed by EdU incorporation and apoptosis by flow cytometry. Results We show that IKKα and IKKβ bind to c-Myc and phosphorylate it at serines 67/71 within a sequence that is highly conserved. Knockout of IKKα decreased c-Myc-activity and increased its T58-phosphorylation, the target site for GSK3β, triggering polyubiquitination and degradation. c-Myc-mutants mimicking IKK-mediated S67/S71-phosphorylation exhibited slower turnover, higher cell proliferation and lower apoptosis, while the opposite was observed for non-phosphorylatable A67/A71-mutants. A significant positive correlation of c-Myc and IKKα levels was noticed in the prostate epithelium of mice and in a variety of human cancers. Conclusions Our data imply that IKKα phosphorylates c-Myc on serines-67/71, thereby stabilizing it, leading to increased transcriptional activity, higher proliferation and decreased apoptosis.

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

Cited by 66 publications

References 62 publications

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity

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