Related Experiment Video

Updated: Mar 7, 2026

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
14:51

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

Published on: June 17, 2022

3.7K

Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and

Alan H Shih1,2, Cem Meydan3,4, Kaitlyn Shank1

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Cancer Discovery
|February 15, 2017
PubMed

Insights

Models of acute myeloid leukemia (AML) with TET2 or IDH2 mutations respond to epigenetic therapy. Combining targeted therapies can improve anti-leukemic activity and restore normal blood cell production.

Area of Science:

  • Hematology
  • Cancer Biology
  • Epigenetics

Background:

  • Genomic studies reveal mutations in TET2 and IDH2 drive altered DNA methylation in acute myeloid leukemia (AML).
  • FLT3-ITD mutations are common in AML and impact disease progression.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting epigenetic pathways and signaling mutations in AML models.
  • To evaluate the efficacy of combining epigenetic therapy with targeted inhibitors.

Main Methods:

  • Utilized AML models with specific mutations (TET2, IDH2, FLT3-ITD).
  • Administered epigenetic drugs (5-azacytidine) and targeted inhibitors (AG-221, FLT3 inhibitors).
  • Assessed antileukemic activity, DNA methylation, transcriptional output, and hematopoiesis restoration.

Main Results:

  • TET2/IDH2-mutated AML models showed sensitivity to 5-azacytidine or AG-221, respectively, leading to reduced leukemic blasts and restored differentiation.
  • Combined therapies (AG-221/5-azacytidine with FLT3 inhibition) reduced mutant allele burden and promoted normal hematopoiesis recovery.
  • Therapeutic interventions normalized aberrant DNA methylation and transcriptional dysregulation.

Conclusions:

  • Targeting both signaling and epigenetic pathways offers a promising strategy for enhancing therapeutic responses in AML.
  • Epigenetic therapy, including 5-azacytidine and IDH2 inhibition, induces differentiation and can be combined with other agents for mechanism-based AML treatment.

More Related Videos

Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors04:36

Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors

Published on: October 17, 2025

1.0K
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors11:15

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors

Published on: September 20, 2016

25.2K

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
9.0K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
6.3K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
2.1K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.3K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.8K
Inhibition of Cdk Activity02:34

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...
6.1K