New Research Explores Targeted Therapy for ASXL1-Mutant CMML

Researchers are studying why some cases of chronic myelomonocytic leukemia (CMML) grow more aggressively than others. A recent study found that certain genetic mutations may activate powerful “switches” that turn on cancer-driving genes.

What is chronic myelomonocytic leukemia (CMML)?

Chronic myelomonocytic leukemia (CMML) is a rare blood cancer that shares features of both leukemia and myelodysplastic syndromes. In CMML, the bone marrow produces too many abnormal white blood cells called monocytes. Over time, these abnormal cells can interfere with normal blood cell production.

What is the ASXL1 mutation?

Some patients with CMML have mutations in the ASXL1 gene. This mutation can cause a more aggressive disease and make it harder to find a therapy that can control the disease long-term. 

ASXL1 mutations can change how DNA is organized and controlled inside the cell without altering the DNA sequence itself. These changes are known as epigenetic changes. 

What are epigenetic changes? 

Epigenetics is a change in what genes are activated that comes after birth or even after years of living. It has been proven to be an evolutionary response that species have to protect themselves from dangers. You can think of it as a system of biological “switches” that turn genes on or off. These switches help cells decide when to grow, divide, or mature.

In cancer some of these switches can become stuck in the “on” position. This causes genes that promote cancer growth to stay active longer than they should. For example, in CMML with ASXL1 mutations, these epigenetic changes can activate cancer-driving genes such as:

• HOXA9, a gene involved in blood cell development
• MEIS1, a gene that works with HOXA9 to support leukemia growth

Using advanced genomics to understand how genes behaved inside cancer cells

To better understand this process, researchers analyzed bone marrow samples from 40 patients with CMML. Of those, 19 patients had ASXL1 mutations, while 21 did not.

Using advanced genomics wanted to identify: 

• Gene activity inside the cancer cells.
• Chemical markers that control gene regulation.
• How accessible certain regions of DNA were inside individual cells.

The study identified 149 regulatory regions linked to genes that drive leukemia growth, including HOXA9 and MEIS1. These regions act like genetic control panels. They help determine when certain genes turn on or off.

Researchers also found 144 regions of DNA that were more accessible in ASXL1-mutant cells than in normal cells. This made it easier for cancer-driving genes to remain active. Several of these regulatory regions were directly connected to the MEIS1 gene, suggesting that they play an important role in leukemia growth.

Why learn about genetic expressions in cancer? 

In this study, researchers also tested a new drug designed to block two proteins that help regulate these cancer-driving regions. This is intended to help shut down the signals that keep leukemia cells growing.

The drug, called EP31670, blocks two important regulators of gene activity:

• p300, a protein involved in gene activation
• BRD4, a protein that helps maintain gene expression

EP31670 was tested in laboratory studies using bone marrow samples from CMML patients. This test showed that the drug worked more effectively in cells with ASXL1 mutations. It also helped cancer cells mature into more normal blood cells rather than continuing to grow uncontrollably.

Discovering specific biological mechanisms that drive CMML can open the possibility of more personalized therapies

Patients with ASXL1 mutations often have more aggressive CMML and fewer effective treatment options. Targeted treatments like EP31670 aim to block the exact signals that cancer cells depend on to survive. 

Researchers are continuing to study this treatment strategy and are exploring its potential in clinical trials. These studies will help determine whether targeting p300 and BRD4 can safely benefit patients with CMML. Explore more clinical trials and use personalized filters based on your specific needs using HealthTree’s Clinical Trial Finder. 

Stay tuned for more updates on emerging therapies, clinical trials, and breakthroughs in blood cancer research. Our community is built by patients, for patients.

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Source: Clone-specific epigenetic regulatory mechanisms in ASXL1-mutant chronic myelomonocytic leukemia