Acute myeloid leukemia (AML), a usually fatal type of blood cancer, arises from hematopoietic (blood-forming) stem cells that have undergone genetic mutations. Mutated “pre-leukemic” stem cells are quite common in healthy older people and usually cause no problems. Some of those cells, however, cause AML. Why?

In a study published online on March 4 in Cancer Cell, Einstein researchers led by Ulrich Steidl, M.D., Ph.D., discovered a mechanism responsible for the transformation of pre-leukemia into AML, along with a possible drug strategy to prevent it.

The scientists’ search for the pre-leukemia-to-AML mechanism focused on a leading suspect: the protein MDMX, which is overexpressed in nearly 90% of all AML patients. They studied five pre-leukemia mouse models, each with a different mutation commonly found in people with pre-leukemia. Some of the animals in all five mouse models were engineered to overexpress MDMX in their pre-leukemic stem cells.

For all five preleukemic models, those animals that over-expressed MDMX developed AML, while animals that did not overexpress MDMX did not develop this aggressive type of blood cancer. The findings confirmed that MDMX overexpression is a crucial mechanism for driving the transition from pre-leukemia to AML, regardless of the different initial mutations.

But how does overabundant MDMX protein make pre-leukemic cells cancerous? The Einstein researchers found that MDMX overexpression triggered the Wnt/β-Catenin signaling pathway (previously implicated in AML and other forms of cancer) to go into overdrive, causing pre-leukemic stem cells to proliferate and become cancerous. Discovery of this “MDMX/ Wnt/β-Catenin axis” in mice has clear implications for people with pre-leukemia.

Patients with myelodysplastic syndrome (MDS)—a common pre-leukemic condition—face a 1 in 3 chance of developing AML. The researchers tested the blood of patients with untreated MDS and divided them into high-MDMX expressors and low-MDMX expressors. Compared with low expressors, patients who were high MDMX expressors had upregulated Wnt/β-Catenin signaling, more serious subtypes of MDS, and were significantly more likely to develop AML.

On the positive side, experiments involving mouse models and human cell lines suggest that combining two investigational drugs—one that inhibits MDMX activity, another that muffles Wnt/β-Catenin signaling—might help prevent AML from occurring in MDS patients who overexpress MDMX.

Dr. Steidl is professor of cell biology and of medicine and the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research at Einstein, associate director for basic science at the Albert Einstein Cancer Center, and associate chair for translational research in oncology at Montefiore. The lead author is Koki Ueda, M.D./Ph.D., a postdoctoral associate in the department of cell biology, who is now moving back to Japan to start his own research group there.