Related Experiment Video
Updated: Oct 1, 2025
10:49
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
18.3K
Targeting Apoptosis Pathways With BCL2 and MDM2 Inhibitors in Adult B-cell Acute Lymphoblastic Leukemia
Helena Hohtari1,2, Matti Kankainen1,2,3,4,5, Shady Adnan-Awad1,2,6
1Translational Immunology Research Program, University of Helsinki, Finland.
Hemasphere
|March 2, 2022
Summary
New drugs targeting antiapoptotic proteins BCL2 and MDM2 show promise for adult acute lymphoblastic leukemia (ALL). Ex vivo drug testing identified specific sensitivities in Philadelphia chromosome-negative and -positive B-ALL, guiding future therapeutic strategies.
Area of Science:
- Hematology
- Molecular Biology
- Pharmacology
Background:
- Treatment outcomes for adult acute lymphoblastic leukemia (ALL) require improvement.
- Identifying novel therapeutic targets is crucial for overcoming treatment resistance in B-ALL.
Purpose of the Study:
- To discover new drug candidates for B-ALL using an ex vivo drug testing platform and molecular profiling.
- To identify gene expression biomarkers associated with drug responses in adult B-ALL patients.
Main Methods:
- Analyzed sensitivity of 18 adult B-ALL patient samples to 64 drugs ex vivo.
- Utilized whole-transcriptome sequencing and public expression data for biomarker analysis.
- Investigated drug responses in relation to Philadelphia chromosome status (Ph+ vs. Ph-).
Main Results:
- Apoptotic modulators targeting BCL2 and MDM2 demonstrated high efficacy.
- Navitoclax and venetoclax were effective in Ph- samples; navitoclax showed greater sensitivity in Ph+ samples.
- BCL2 was downregulated, while BCL-W and BCL-XL were upregulated in Ph+ ALL compared to Ph- ALL.
- Idasanutlin (MDM2 inhibitor) showed sensitivity in most samples, with increased MDM2 expression in B-ALL.
- Combination therapy with BCL2 and MDM2 inhibitors exhibited synergy in B-ALL cell lines.
Conclusions:
- Antiapoptotic proteins BCL2 and MDM2 are promising therapeutic targets for adult B-ALL.
- Differential expression of BCL2 family proteins contributes to varying drug responses based on Philadelphia chromosome status.
- Combined targeting of BCL2 and MDM2 pathways may offer a synergistic therapeutic strategy for B-ALL.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
6.9K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.9K
02:57Targeted Cancer Therapies
7.9K
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...
There are several types of targeted therapies against...
7.9K
02:50Combination Therapies and Personalized Medicine
5.1K
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...
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...
5.1K
02:34Inhibition of Cdk Activity
5.0K
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...
5.0K
02:23Abnormal Proliferation
4.7K
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...
4.7K