Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning anti-apoptotic proteins BCL2 and MCL1 are frequently expressed. Here, we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find clinical samples have frequent co-expression of MCL1 and BCL2, suggesting therapeutic strategies targeting only one will lead to treatment failures due to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest anti-tumor activity against most DLBCL lines and resulted in compensatory up-regulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent anti-tumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients.Leukemia accepted article preview online, 17 April 2015. doi:10.1038/leu.2015.99.
Pharmacology, Toxicology and Pharmaceutical Science
6
9%
Engineering
2
3%
Other
1
2%
Unknown
14
21%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 19. 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 09 September 2025.
All research outputs
#2,389,685
of 33,779,198 outputs
Outputs from Leukemia
#561
of 7,207 outputs
Outputs of similar age
#24,994
of 306,305 outputs
Outputs of similar age from Leukemia
#5
of 61 outputs
Altmetric has tracked 33,779,198 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 92nd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 7,207 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 9.8. This one has done particularly well, scoring higher than 92% 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 306,305 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 91% of its contemporaries.
We're also able to compare this research output to 61 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 91% of its contemporaries.
