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Inhibition of Cdk Activity

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

Epigenetic Regulation

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...

Anaphase Promoting Complex

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...

M-Cdk Drives Transition Into Mitosis

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M cyclin...

S-Cdk Initiates DNA Replication

S-Cdk Initiates DNA Replication

The cell cycle is a series of events leading to DNA duplication followed by the division of cell content to form two daughter cells. The cell cycle progresses in four stages—the cell increases in size (gap 1 or G1-phase), duplicates its DNA (synthesis or S-phase), prepares to divide (gap 2 or G2-phase), and divides (mitosis or M-phase).
Two states at the origin of replication
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Positive Regulator Molecules

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.

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Related Experiment Video

Updated: May 23, 2025

A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers

A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers

Published on: September 26, 2019

Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12.

Selina Troester¹, Thomas Eder¹, Nadja Wukowits¹

¹Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.

Nature Communications

|May 19, 2025

Summary

Nucleoporin 98 (NUP98) fusion oncoproteins drive pediatric acute myeloid leukemia (AML). Targeting CDK12, a direct NUP98::KDM5A target, induces DNA damage and AML cell death, revealing a new therapeutic vulnerability.

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Last Updated: May 23, 2025

A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers

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Published on: September 26, 2019

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Published on: September 20, 2018

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Published on: June 27, 2020

Area of Science:

Hematology
Molecular Biology
Epigenetics

Background:

Nucleoporin 98 (NUP98) fusion oncoproteins are key drivers of pediatric acute myeloid leukemia (AML), associated with poor prognosis.
NUP98-fusion AML exhibits a distinct epigenetic signature, including enhanced accessibility of hematopoietic stem cell genes and activating histone marks.

Purpose of the Study:

To identify epigenetic programs and transcriptional targets directly regulated by the NUP98::KDM5A fusion oncoprotein.
To uncover direct NUP98::KDM5A target genes essential for AML cell proliferation.
To identify actionable therapeutic vulnerabilities in NUP98::KDM5A-driven AML.

Main Methods:

Utilized a ligand-induced degradation model for NUP98::KDM5A in AML.
Employed CUT&Tag and nascent RNA-seq to map epigenetic and transcriptional regulation.
Performed genome-wide CRISPR/Cas9 screening to identify direct target genes.

Main Results:

Identified 12 direct NUP98::KDM5A target genes crucial for AML cell growth.
Validated cyclin-dependent kinase 12 (CDK12) as a druggable target in NUP98::KDM5A-expressing AML.
Demonstrated that CDK12 inactivation leads to increased DNA damage and AML cell death.

Conclusions:

NUP98::KDM5A directly regulates a core set of genes essential for AML pathogenesis.
CDK12 represents a promising therapeutic vulnerability for AML patients with oncogenic NUP98 fusions.
Targeting CDK12 offers a potential strategy to induce synthetic lethality in NUP98-fusion AML.