Related Experiment Video

Updated: Jun 3, 2025

Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
09:16

Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells

Published on: September 1, 2019

7.5K

Inhibiting H3K27 Demethylases Downregulates CREB-CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic

Juan Lazaro-Navarro1,2, Clara Alcon3,4, Mathurin Dorel5

  • 1Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Cancer Medicine
|January 10, 2025
PubMed
Abstract

Insights

This study shows that inhibiting H3K27 demethylase with GSK-J4 can overcome drug resistance in acute lymphoblastic leukemia (ALL). High CREBBP expression predicts sensitivity to GSK-J4, suggesting it as a biomarker for treatment.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Hematology

Background:

  • CREB binding protein (CREBBP) is a crucial epigenetic regulator implicated in relapsed acute lymphoblastic leukemia (ALL).
  • Targeting epigenetic signaling offers a novel strategy to combat drug resistance in ALL.
  • GSK-J4, an H3K27 histone demethylase inhibitor, has demonstrated anti-tumor effects in preclinical cancer models.

Purpose of the Study:

  • To investigate the therapeutic potential of GSK-J4 in ALL.
  • To characterize the molecular mechanisms underlying GSK-J4's anti-leukemic effects.
  • To identify biomarkers for predicting response to GSK-J4 treatment.

Main Methods:

  • Drug response profiling, CRISPR-Dropout Screening, BH3 profiling, and immunoblotting were employed.
  • Experiments were conducted on ALL cell lines and patient-derived samples.
  • Analysis focused on the effects of GSK-J4 on CREB, CREBBP, and apoptosis-related proteins.

Main Results:

  • GSK-J4 was found to downregulate CREB and CREBBP in B-cell precursor-ALL (BCP-ALL).
  • High CREBBP expression correlated with increased sensitivity to GSK-J4 and decreased sensitivity to dexamethasone.
  • GSK-J4 treatment induced dependency on Bcl-2 and Bcl-XL, leading to apoptosis.

Conclusions:

  • H3K27 demethylase inhibition represents a promising treatment strategy for refractory ALL.
  • CREBBP serves as a potential biomarker for predicting patient response to GSK-J4.
  • Combination therapy with GSK-J4, venetoclax, and navitoclax demonstrated synergistic effects.
Keywords:
apoptosisdrug discovery and deliveryepigeneticsleukemia

More Related Videos

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype14:51

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

Published on: June 17, 2022

3.2K
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.1K

Related Concept Videos

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...
3.2K
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...
4.4K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.0K
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...
7.4K
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...
4.6K
Chromatin Modification in iPS Cells01:32

Chromatin Modification in iPS Cells

Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
1.6K