How Scientists Are Targeting CREBBP Mutations in Leukemia
Imagine a young patient successfully treated for leukemia, only to have the cancer return, this time resistant to conventional chemotherapy.
This devastating scenario plays out all too often in relapsed acute lymphoblastic leukemia (ALL), particularly in cases involving mutations in a gene called CREBBP. For the thousands of children and adults affected by B-cell acute lymphoblastic leukemia (B-ALL) each year, these CREBBP mutations represent a critical barrier to cure, appearing in up to 18% of relapsed cases 8 .
CREBBP mutations identified in relapsed B-ALL cases, driving treatment resistance.
Innovative approaches revealing new therapeutic vulnerabilities.
Under normal circumstances, the CREBBP protein (pronounced "creb-b-p") acts as a master cellular regulator with remarkable versatility. Think of it as both a construction supervisor and quality control manager for your DNA—it helps activate the right genes at the right times while maintaining the proper structure of our genetic material 7 .
CREBBP's importance stems from its multiple functions. It serves as a scaffold protein that brings together various cellular machinery needed to read genetic information. Additionally, it acts as a histone acetyltransferase, meaning it adds chemical tags to proteins called histones around which DNA is wrapped 7 .
In leukemia, particularly B-ALL, CREBBP frequently acquires loss-of-function mutations—genetic errors that render the protein ineffective. These mutations are especially common in relapsed cases, suggesting they provide cancer cells with a survival advantage during chemotherapy 8 .
Researchers began by selecting the 697 B-ALL cell line, derived from a patient with high-risk relapsed E2A::PBX1 B-ALL 2 . They used CRISPR-Cas9 gene editing to create two distinct variations:
The research team subjected these engineered cells to a targeted drug screen focused on clinically actionable compounds:
| Drug Category | Example Drug | CREBBP Wild-Type IC50 | CREBBP Mutant IC50 | Fold Change |
|---|---|---|---|---|
| BCL2 Inhibitor | Venetoclax | 200 nM | 20 nM | 10-fold decrease |
| Epigenetic Inhibitor | A485 (CREBBP/EP300) | 500 nM | 100 nM | 5-fold decrease |
| Glucocorticoid | Dexamethasone | 50 nM | 20 nM | 2.5-fold decrease |
| Conventional Chemotherapy | Cytarabine | 1 μM | 1.2 μM | Minimal change |
Most strikingly, Venetoclax showed a 10-fold increase in potency against CREBBP-mutated cells compared to their wild-type counterparts 2 .
Studying complex genetic mutations like those in CREBBP requires specialized research tools.
| Research Tool | Function in CREBBP Research | Example Use |
|---|---|---|
| Isogenic Cell Lines | Genetically matched except for CREBBP status | Isolating specific effects of CREBBP mutations 2 |
| CRISPR-Cas9 Gene Editing | Introduce specific mutations into CREBBP gene | Creating disease models with patient-relevant mutations 2 |
| CREBBP/EP300 Inhibitors | Chemically block CREBBP protein function | Testing pharmacologic inhibition effects 2 5 |
| BCL2 Inhibitors | Block anti-cell death protein BCL2 | Targeting synthetic lethality in CREBBP-mutated cells 2 |
| RNA Sequencing | Comprehensive gene expression profiling | Identifying molecular pathways altered by CREBBP mutation 2 |
The discovery that CREBBP-mutated B-ALL cells show heightened sensitivity to Venetoclax represents a potential paradigm shift in treating this high-risk leukemia subtype 2 .
Even more intriguing, pharmacological inhibition of CREBBP could sensitize even CREBBP-wild-type B-ALL cells to Venetoclax, potentially expanding this approach to a broader patient population 2 .
Follow-up investigations revealed that CREBBP-mutated cells undergo significant metabolic reprogramming, particularly in lipid metabolism, which predisposes them to ferroptotic cell death 2 .
This represents a classic synthetic lethal interaction—where the combination of two perturbations causes cell death, while either alone does not.
| Approach | Mechanism | Development Stage |
|---|---|---|
| Venetoclax Monotherapy | BCL2 inhibition inducing ferroptosis | Preclinical validation 2 |
| CREBBP Inhibitor + Venetoclax | Pharmacologic CREBBP inhibition with BCL2 targeting | Preclinical testing 2 |
| Ep300-specific inhibitors | Targeting CREBBP paralogue | Early clinical trials 5 |
| Histone Deacetylase Inhibitors | Compensating for acetyltransferase deficiency | Preclinical investigation |
The journey to understand CREBBP mutations in relapsed acute lymphoblastic leukemia demonstrates how modern science can transform a dire clinical problem into a landscape of therapeutic opportunity.
From discovery of resistance mechanisms to identifying therapeutic vulnerabilities
Potential for accelerated translation from lab findings to patient treatments
Optimizing combination therapies and identifying predictive biomarkers
What began as an observation about a gene associated with treatment failure has evolved into a promising new frontier—one that offers real hope for patients facing this challenging form of leukemia.