Can Menin Inhibitors Become a New Treatment Option for Myeloproliferative Neoplasms?

Menin inhibitors are a new type of targeted therapy currently approved to treat acute myeloid leukemia (AML). They act by targeting specific genetic mutations in cancer cells. New research suggests that the use of menin inhibitors could be expanded to other diseases, such as myeloproliferative neoplasms (MPNs).

What are myeloproliferative neoplasms (MPNs)?

Myeloproliferative neoplasms, or MPNs, are blood cancers in which the bone marrow makes too many blood cells. Depending on the type, this may include too many red blood cells, white blood cells, or platelets.

Many MPNs have mutations in genes such as JAK2, CALR, or MPL. These changes can cause certain blood-forming cells, especially megakaryocytes, the cells that produce platelets, to grow and multiply more than they should.

Over time, this overgrowth can lead to symptoms such as fatigue, blood clots, bleeding problems, an enlarged spleen, and bone marrow fibrosis (scarring).

What is menin and why does it matter in blood cancer?

Menin is a protein that helps regulate the activation of certain genes within cells. It plays an important role in blood cell development. This process is called hematopoiesis.Menin inhibitors are designed to block the activity of this protein. 

For example, revumenib, is already approved by the U.S. Food and Drug Administration (FDA) for certain types of acute myeloid leukemia (AML), a fast-growing blood cancer. 

Researchers noticed a side effect of revumenib that could help people with MPNs: low platelet counts. In MPNs, platelet-producing cells are overactive. 

How do menin inhibitors affect platelet-producing cells?

To understand how menin inhibitors affect platelet-producing cells, researchers tested revumenib in the lab on human blood-forming stem cells. There was a significant decrease in early platelet-forming cells called megakaryocyte progenitor cells. Revumenib also reduced the development of mature megakaryocytes, the cells that release platelets into the bloodstream.

Although platelet production was suppressed, other types of blood-forming cells were not affected. This suggests that menin inhibition selectively targets megakaryocytes rather than broadly suppressing the entire bone marrow.A second menin inhibitor, ziftomenib, showed similar effects. 

Could menin inhibition help treat MPNs?

Because megakaryocyte overgrowth is a hallmark of MPNs, researchers tested revumenib in laboratory samples from patients with MPNs carrying CALR and JAK2 mutations.

In these samples, revumenib reduced the growth of megakaryocytes and their progenitors.

The team then studied revumenib in several mouse models. In mouse models, researchers modify mouse cells to look like human MPN cells. In this study, they had MPL and JAK2 mutations. :

In these mice, researchers found: 

• Reduced white blood cell and platelet counts
• A 5.7-fold decrease in megakaryocytes in bone marrow
• Elimination of bone marrow fibrosis
• Normalization of hemoglobin and red blood cell counts in JAK2-driven disease
• Significant reduction in spleen size (up to 4.3-fold)
• Improved overall survival

Another interesting finding was a reduction in levels of fibrogenic cytokines. These are proteins that promote scarring. There was also a significant decrease in transforming growth factor beta, which drives fibrosis or scarring. 

Even more promising, combining revumenib with ruxolitinib (a commonly used JAK inhibitor for MPNs) led to deeper reductions in abnormal blood counts and further improvements in spleen size and bone marrow fibrosis.

Human clinical trials testing revumenib specifically for MPN are still needed to confirm safety and effectiveness.

Find out which clinical trials you are eligible for with HealthTree’s Clinical Trial Finder.

Stay informed for more encouraging MPN news with HealthTree 

Research continues to uncover the biological “weak spots” of these diseases, bringing us closer to more precise, personalized treatments.

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Source: Menin inhibition as a new therapeutic option for the myeloproliferative neoplasms