Inhibiting protein to treat myeloproliferative neoplasms shows preclinical promise

Inhibiting menin, a protein that supports leukemia growth and is already targeted to treat some forms of leukemia, also holds promise for treating myeloproliferative neoplasms. A new study from scientists at St. Jude Children’s Research Hospital showed that inhibiting menin significantly extended survival and reversed multiple disease features in preclinical models. The findings were published today in Cancer Cell.

Menin is best known as a therapeutic vulnerability in certain types of acute leukemia, including those with KMT2A gene rearrangements or NPM1 mutations. Menin inhibitors, such as revumenib, have greatly improved treatment for these cancers and are approved by the Food and Drug Administration (FDA). However, menin inhibition can reduce megakaryocytes (normal platelet-forming cells) and decrease platelet counts. Producing too many megakaryocytes is a hallmark of diseases called myeloproliferative neoplasms, which are slow-developing, rare blood cancers.

John Crispino, Ph.D., MBA, St. Jude Division of Experimental Hematology director and Department of Hematology member, tested whether inhibiting menin could be a viable therapeutic strategy for myeloproliferative neoplasms.

“We were surprised to find that menin inhibition produced one of the best preclinical results we’ve ever seen for myeloproliferative neoplasms,” Crispino said. “We saw very strong activity, extending survival, preventing fibrosis and normalizing blood cell counts.”

The researchers conducted experiments to treat mice with revumenib by itself or in combination with standard therapy. They also tested removing the menin gene itself. They found that most models survived to the end of the study and signs of disease, such as fibrosis, disappeared in nearly all cases, including models created using samples from human tumors.

Menin targets cancers at their source

The researchers found no significant toxicity, and because revumenib is already FDA-approved, the findings may help accelerate efforts to test menin inhibition in clinical trials for patients with myeloproliferative neoplasms. Clinical trials are a pivotal step in testing whether what the researchers see in the laboratory will hold true in patients.

However, Crispino cautioned that previous findings from his lab supporting the use of aurora kinase inhibition (a protein involved in megakaryocyte development) were less effective in a clinical trial. Despite that, findings from the current study provide a plausible explanation for why that approach did not work—and a reason to expect that menin inhibition will perform better in the clinic.

“When we inhibited aurora kinase, it was like we were bailing water from an overflowing sink by targeting only later-stage megakaryocytes,” Crispino said. “We found that when we inhibited menin, we were turning off the faucet—we were killing off the early megakaryocyte progenitor cells that most other malignant cells were coming from and stopping the number of cancerous cells from overflowing.”

By targeting earlier progenitor cells, menin inhibition may strike closer to the source of disease. That distinction provides a rationale for further investigation, especially for patients whose diseases have few effective treatment options.

“We are really excited that this could make a difference for patients,” Crispino said. “Menin inhibition has already been a breakthrough therapy for other aggressive leukemias that we treat at St. Jude every day, so we hope that we can leverage that experience to get this into clinical trials and test it as another agent to potentially help people with myeloproliferative neoplasms.”

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Gaby Clark

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Andrew Zinin

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