CDK9: a signaling hub for transcriptional control

Bacon, Curtis W.; D’Orso, Iván

doi:10.1080/21541264.2018.1523668

Cited by 157 publications

(135 citation statements)

References 124 publications

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“…5 CDK9 positively regulates transcription elongation through phosphorylation of serine 2 of RNA polymerase II (RNAPII). 6 Given the central role of CDK9 in the leukemic MLL-r gene-expression program, 7 and the well-described ability of CDK9 inhibitors to reduce levels of the short-lived prosurvival protein MCL1, 8 a number of CDK9 inhibitors have been selected for clinical trials focusing on acute leukemias, including those with MLL-r. 8,9 In MLL-r leukemia, the bromodomain and extraterminal (BET) family member bromodomain-containing 4 (BRD4) 10 acts to recruit PTEFb to superenhancers and together with CDK9 drives increased expression of many oncogenes including MYC. 11,12 The roles of CDK9 and BRD4 in MLL-r leukemias present a strong case for testing inhibitors of these proteins in combination as a potential treatment of MLL-r acute leukemias.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

McCalmont

Jones

et al. 2020

Blood Advances

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Section: Introductionmentioning

confidence: 99%

Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

McCalmont

Jones

et al. 2020

Blood Advances

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“…In contrast, total levels of RNA pol II in chromatin did not change ( Figure 5C). CDK9 is the mayor kinase phosphorylating Ser2 of the CTD (28). Lack of prefoldin did not produce significant changes in the cellular levels of CDK9 ( Supplementary Figure S8A-B).…”

Section: Prefoldin Is Present In the Body Of Transcribed Genes And Comentioning

confidence: 98%

Human prefoldin modulates co-transcriptional pre-mRNA splicing

Payán-Bravo

Peñate

Cases

et al. 2020

Preprint

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Prefoldin is a heterohexameric complex conserved from archaea to humans that plays a cochaperone role during the cotranslational folding of actin and tubulin monomers. Additional functions of prefoldin in the cell nucleus have been described, including a positive contribution to transcription elongation and chromatin dynamics in yeast. Here we show that prefoldin depletion provoked transcriptional alterations across the genome of human cells. Severe pre-mRNA splicing defects were also detected, particularly under serum stimulation conditions. We found a significant impairment of co-transcriptional splicing during transcription elongation, that explains why the expression of long genes with a high number of introns was affected the most. We detected prefoldin binding to the gene body of transcribed genes and found that its lack caused significant decrease in the levels of Ser2 phosphorylation of the RNA polymerase II carboxiterminal domain. Moreover, lack of prefoldin reduced the association of splicing factor U2AF65 with chromatin, an association that is known to be dependent on Ser2 phosphorylation. Considered altogether the reported results indicate that human prefoldin is able to modulate gene expression by influencing phosphorylation of elongating RNA polymerase II, and thereby regulating co-transcriptional splicing efficiency.

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“…Inhibition of CDK7, CDK8, and CDK9 have been of particular interest in AML (59,133,134). These CDKs phosphorylate the carboxyl terminal domain (CTD) of RNA polymerase II (RNA Pol II), to facilitate the production of mature transcripts (128,129,135,136). These transcriptional CDKs have been found to be dysregulated in AML (58,137).…”

Section: Transcriptional Cdksmentioning

confidence: 99%

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Tibes

Bogenberger

2019

Front. Oncol.

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Acute myeloid leukemia (AML) is the most common adult acute leukemia. Survival remains poor, despite decades of scientific advances. Cytotoxic induction chemotherapy regimens are standard-of-care for most patients. Many investigations have highlighted the genomic heterogeneity of AML, and several new targeted therapeutic options have recently been approved. Additional novel therapies are showing promising clinical results and may rapidly transform the therapeutic landscape of AML. Despite the emerging clinical success of B-cell lymphoma (BCL)-2 targeting in AML and a large body of preclinical data supporting myeloid leukemia cell (MCL)-1 as an attractive therapeutic target for AML, MCL-1 targeting remains relatively unexplored, although novel MCL-1 inhibitors are under clinical investigation. Inhibitors of cyclin-dependent kinases (CDKs) involved in the regulation of transcription, CDK9 in particular, are being investigated in AML as a strategy to target MCL-1 indirectly. In this article, we review the basis for CDK inhibition in oncology with a focus on relevant preclinical mechanism-of-action studies of CDK9 inhibitors in the context of their therapeutic potential specifically in AML.

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CDK9: a signaling hub for transcriptional control

Cited by 157 publications

References 124 publications

Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

Human prefoldin modulates co-transcriptional pre-mRNA splicing

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

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