Oncotarget: Cell cycle arrest and anaphase catastrophe in malignant T-cells

Oncotarget published "NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells" which reported that peripheral T-cell lymphoma is characterized by poor outcomes.

Here, the authors report that PTCL is characterized by an increased rate of chromosomal instability. They identified p27Kip1 as a mediator of anaphase catastrophe in these cells.

The authors report that PTCL is characterized by an increased rate of chromosomal instability

Dr. Alexey V. Danilov from The City of Hope Comprehensive Cancer Center said, "Peripheral T-cell lymphoma (PTCL) is an aggressive subset of non-Hodgkin lymphomas (NHL) characterized by poor outcomes."

Aberrant T-cell receptor and JAK-STAT signaling, genomic abnormalities targeting epigenetic modifiers and chromatin remodeling and altered cellular metabolism result in deregulated cell cycle, enhanced cell survival and proliferation in PTCL. The substantial genetic and biologic heterogeneity hinders success of targeted therapies in this disease and chemotherapy remains standard in both de novo and relapsed/refractory settings.

This pathway preferentially eliminates aneuploid cancer cells by antagonizing clustering of supernumerary centrosomes during mitosis, forcing cells to undergo multipolar divisions. However, it is not known if anaphase catastrophe occurs in NHL cells, and whether it may be induced by pharmacologic induction of endogenous CDK inhibitors in a cell.

Figure 4: Malignant T-cells undergo anaphase catastrophe following NAE inhibition. (A) Cells were incubated with the indicated concentration of pevonedistat or vehicle control for 24 hours. Cells were immunostained with γ-tubulin (pink) and counterstained with DAPI (blue). Total anaphases were counted (50) and the proportion of multipolar anaphases is shown. Data are the mean ± SEM of at least 3 independent experiments. Representative examples of normal mitosis and multipolar anaphase are shown. (B) Jurkat and SR cells were transfected with a lentiviral CRISPR toolbox to achieve knockout of p27, or vector control. Cells were treated with pevonedistat as indicated, proteins were lysed and subjected to immunoblotting. (C) Cells were treated with pevonedistat for 24 hours and subjected to cell cycle profiling with propidium iodide staining. A summary of three independent experiments is shown. (D) p27-deficient cells were incubated with 0.25 μM pevonedistat or vehicle control for 24 hours. Cells were immunostained with γ-tubulin and counterstained with DAPI. Total anaphases were counted (50) and the proportion of multipolar anaphases is shown. Data are the mean ± SEM of six (Jurkat) and three (SR) independent experiments. (E) Jurkat cells were treated with 0.25 μM pevonedistat or vehicle control for 48 hours. Apoptosis was determined by Annexin-V staining. Data are mean ± SEM of 6 independent experiments. ^*p < 0.05 and ^**p < 0.01 vs. control.

Pevonedistat forms a covalent adduct with NEDD8, resulting in NAE inhibition and accumulation of CRL substrates. CDT1, CDK inhibitors p21Cip1/p27Kip1 as well as checkpoint kinase Wee1 are among the CRL substrates which are increased following NAE inhibition.

The Danilov Research Team concluded in their Oncotarget Research Output, "we demonstrate that PTCL exhibits pronounced chromosomal mis-segregation. Targeting NAE with pevonedistat leads to cell cycle arrest and anaphase catastrophe in neoplastic T-cells. This effect, possibly coupled with immunomodulatory activity of pevonedistat recently described by our group [18], justifies continued exploration of pevonedistat as a novel therapeutic approach in T-cell NHL."

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DOI - https://doi.org/10.18632/oncotarget.28063

Full text - https://www.oncotarget.com/article/28063/text/

Correspondence to - Alexey V. Danilov - adanilov@coh.org

Keywords - pevonedistat, T-cell lymphoma, chromosomal instability, anaphase catastrophe

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