Targeting RUNX1-Mutated Refractory AML

Acute myeloid leukemia (AML) that harbors a RUNX1 mutation, but is cytogenically normal, has a poor diagnosis because it is often refractory to chemotherapy.

Acute myeloid leukemia (AML) that harbors a RUNX1 mutation, but is cytogenically normal, has a poor diagnosis because it is often refractory to chemotherapy. To understand what makes this tumor type particularly unresponsive to cytotoxic therapy, researchers have created the first mouse model of this subtype of AML to understand its underlying biology to design better therapies.

The results of the preclinical study is published in the July 15, 2015 online edition of PLOS ONE.1

Umayal Sivagnanalingam, BS, and Jason H. Mendler, MD, PhD, both of the University of Rochester’s Wilmot Cancer Institute in Rochester, NY, and colleagues injected a patient-derived RUNX1-mutated cytogenetically normal AML cell line into mice to create xenografts with leukemia in the bone marrow, spleen, and peripheral blood.2 As patients with this type of AML, the leukemia mice were refractory to anthracycline-based chemotherapy. Even though the chemotherapy resulted in clearance of the AML from the spleen and peripheral blood within 4 days following therapy, AML still persisted in the bone marrow.

Chemotherapy may not be able to cure RUNX1-mutated AML because cytotoxic agents cannot target the leukemia cell populations in the marrow, responsible for the regeneration of AML cells. Supporting this hypothesis, the authors found that the AML cells in the bone marrow left after therapy are able to initiate new disease in secondary mouse transplants. In other words, the AML cells derived from the bone marrow of chemotherapy-treated mice engrafted into new mice, resulting in AML.

The xenograft mice had a short period to AML development, high burden of disease, and poor survival following chemotherapy-based treatment.

“Like all cancers, leukemia is not a one-size-fits-all, and therefore it’s important to find better ways to study high-risk subtypes of the disease,” said Dr. Mendler in a statement. “We believe our mouse model will allow us to quickly define new ways to target this challenging disease.”

The study authors performed whole-genomic sequencing of the human cell line, identifying novel mutations including in ASXL1, CEBPA, GATA2, and SETBP1, which have not been previously reported in other studies.

About 15% of patients diagnosed with AML have a mutation in the RUNX1 gene that is associated with the inability to clear leukemic cells from the bone marrow. Still, how important the RUNX1 mutation is for driving AML or residual disease is not known, nor is how this mutation interacts with either wild-type or mutated genes to drive the disease.

The researchers are currently using this mouse model to better understand the molecular mechanism of the persistence of AML in the bone marrow.

According to the scientists, the mouse model can serve as a platform to test novel therapeutics for their ability to eradicate bone marrow leukemic cells. Dr. Mendler’s laboratory has started to use this model as part of a preclinical collaboration with industry to identify potential therapies for RUNX1-mutated AML.