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X Demographics
Mendeley readers
Attention Score in Context
| Title |
CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma
|
|---|---|
| Published in |
Molecular Cancer, March 2023
|
| DOI | 10.1186/s12943-023-01762-6 |
| Pubmed ID | |
| Authors |
Elana Thieme, Nur Bruss, Duanchen Sun, Edward C. Dominguez, Daniel Coleman, Tingting Liu, Carly Roleder, Melissa Martinez, Krystine Garcia-Mansfield, Brian Ball, Patrick Pirrotte, Lili Wang, Zheng Xia, Alexey V. Danilov |
| Abstract |
Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL. |
X Demographics
The data shown below were collected from the profiles of 6 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 4 | 67% |
| Unknown | 2 | 33% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 4 | 67% |
| Scientists | 2 | 33% |
Mendeley readers
The data shown below were compiled from readership statistics for 17 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 17 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 5 | 29% |
| Student > Bachelor | 3 | 18% |
| Student > Doctoral Student | 1 | 6% |
| Student > Ph. D. Student | 1 | 6% |
| Professor > Associate Professor | 1 | 6% |
| Other | 0 | 0% |
| Unknown | 6 | 35% |
| Readers by discipline | Count | As % |
|---|---|---|
| Pharmacology, Toxicology and Pharmaceutical Science | 3 | 18% |
| Biochemistry, Genetics and Molecular Biology | 2 | 12% |
| Medicine and Dentistry | 2 | 12% |
| Agricultural and Biological Sciences | 1 | 6% |
| Physics and Astronomy | 1 | 6% |
| Other | 1 | 6% |
| Unknown | 7 | 41% |
Attention Score in Context
This research output has an Altmetric Attention Score of 4. 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 01 April 2023.
All research outputs
#7,260,892
of 23,986,470 outputs
Outputs from Molecular Cancer
#528
of 1,799 outputs
Outputs of similar age
#125,826
of 402,460 outputs
Outputs of similar age from Molecular Cancer
#11
of 32 outputs
Altmetric has tracked 23,986,470 research outputs across all sources so far. This one has received more attention than most of these and is in the 69th percentile.
So far Altmetric has tracked 1,799 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.2. This one has gotten more attention than average, scoring higher than 70% 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 402,460 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 68% of its contemporaries.
We're also able to compare this research output to 32 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 68% of its contemporaries.