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Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models

Overview of attention for article published in Journal of Hematology & Oncology, June 2016
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (80th percentile)

Mentioned by

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4 patents

Citations

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58 Dimensions

Readers on

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94 Mendeley
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Title
Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models
Published in
Journal of Hematology & Oncology, June 2016
DOI 10.1186/s13045-016-0280-3
Pubmed ID
Authors

Christian Lehmann, Thomas Friess, Fabian Birzele, Anna Kiialainen, Markus Dangl

Abstract

Venetoclax, a small molecule BH3 mimetic which inhibits the anti-apoptotic protein Bcl-2, and idasanutlin, a selective MDM2 antagonist, have both shown activity as single-agent treatments in pre-clinical and clinical studies in acute myeloid leukemia (AML). In this study, we deliver the rationale and molecular basis for the combination of idasanutlin and venetoclax for treatment of p53 wild-type AML. The effect of idasanutlin and venetoclax combination on cell viability, apoptosis, and cell cycle progression was investigated in vitro using established AML cell lines. In vivo efficacy was demonstrated in subcutaneous and orthotopic xenograft models generated in female nude or non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Mode-of-action analyses were performed by means of cell cycle kinetic studies, RNA sequencing as well as western blotting experiments. Combination treatment with venetoclax and idasanutlin results in synergistic anti-tumor activity compared with the respective single-agent treatments in vitro, in p53 wild-type AML cell lines, and leads to strongly superior efficacy in vivo, in subcutaneous and orthotopic AML models. The inhibitory effects of idasanutlin were cell-cycle dependent, with cells arresting in G1 in consecutive cycles and the induction of apoptosis only evident after cells had gone through at least two cell cycles. Combination treatment with venetoclax removed this dependency, resulting in an acceleration of cell death kinetics. As expected, gene expression studies using RNA sequencing showed significant alterations to pathways associated with p53 signaling and cell cycle arrest (CCND1 pathway) in response to idasanutlin treatment. Only few gene expression changes were observed for venetoclax treatment and combination treatment, indicating that their effects are mediated mainly at the post-transcriptional level. Protein expression studies demonstrated that inhibition of the anti-apoptotic protein Mcl-1 contributed to the activity of venetoclax and idasanutlin, with earlier inhibition of Mcl-1 in response to combination treatment contributing to the superior combined activity. The role of Mcl-1 was confirmed by small hairpin RNA gene knockdown studies. Our findings provide functional and molecular insight on the superior anti-tumor activity of combined idasanutlin and venetoclax treatment in AML and support its further exploration in clinical studies.

Mendeley readers

The data shown below were compiled from readership statistics for 94 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 94 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 19 20%
Student > Master 12 13%
Student > Bachelor 11 12%
Researcher 9 10%
Student > Postgraduate 8 9%
Other 14 15%
Unknown 21 22%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 29 31%
Medicine and Dentistry 21 22%
Pharmacology, Toxicology and Pharmaceutical Science 8 9%
Agricultural and Biological Sciences 7 7%
Chemistry 2 2%
Other 4 4%
Unknown 23 24%

Attention Score in Context

This research output has an Altmetric Attention Score of 9. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 03 March 2022.
All research outputs
#3,002,443
of 21,318,320 outputs
Outputs from Journal of Hematology & Oncology
#191
of 1,088 outputs
Outputs of similar age
#57,059
of 288,295 outputs
Outputs of similar age from Journal of Hematology & Oncology
#1
of 1 outputs
Altmetric has tracked 21,318,320 research outputs across all sources so far. Compared to these this one has done well and is in the 84th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,088 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 7.8. This one has done well, scoring higher than 81% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 288,295 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 80% of its contemporaries.
We're also able to compare this research output to 1 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them