Children’s Research Hospital
John Schuetz, PhD Photo from St. Jude
Researchers say they have uncovered a target to overcome drug resistance in acute myeloid leukemia (AML).
The team discovered how a linkage between 2 proteins enables AML cells to resist chemotherapy and showed that disrupting the linkage could render the cells vulnerable to treatment.
The researchers believe their discovery could lead to drugs to enhance chemotherapy in patients with AML and other cancers.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described this research in Nature Communications.
The team launched their experiments based on previous findings that a protein called ABCC4 was greatly elevated in aggressive cases of AML.
Dr Schuetz and his colleagues searched for other proteins that might interact with ABCC4 and enable its function. The team’s screening of candidate proteins yielded one, MPP1, which was also greatly increased in AML.
The researchers found the 2 proteins are connected, and the connection enables cells to assume the characteristics of highly proliferative leukemia cells.
These experiments involved genetically altering hematopoietic progenitor cells to have high MPP1 and ABCC4 levels. The cells were grown in culture and then replated to see if they would continue to grow, as such self-renewal is a hallmark of leukemia cells.
The researchers found that serial regrowth depended on the cells having high levels of both ABCC4 and MPP1.
“Typically, if you take normal progenitors and you replate, you could do that one time, maybe twice,” Dr Schuetz said. “But our big surprise was that overexpressing MPP1—analogous to what you would see in leukemia—allows those progenitors to self-renew, to be replated over and over, to form new colonies.”
The experiments also revealed that MPP1 and ABCC4 functioned at the cell membrane, where they could play a role in the machinery that would rid the leukemia cells of chemotherapy drugs.
“When we disrupted their interaction, ABCC4 moved off the membrane and the cells became more sensitive to drugs used in AML—drugs that are pumped out of the cell by ABCC4,” Dr Schuetz said.
By screening thousands of compounds, the researchers identified some that could disrupt the ABCC4-MPP1 connection. One, called Antimycin-A, reversed drug resistance in AML cell lines and in cells from AML patients.
Antimycin-A is too toxic to be used in chemotherapy, but the researchers believe identification of the compound should aid the search for other, less-toxic drugs to disrupt the ABCC4-MPP1 interaction.
The team’s findings could also enable clinicians to identify AML patients with high levels of ABCC4 and MPP1. In such patients, drugs that disrupt ABCC4-MPP1 might enhance the effectiveness of standard chemotherapy, Dr Schuetz said.
He also noted that other cancers, including breast and colon cancer and medulloblastoma, show high levels of both ABCC4 and MPP1. Chemotherapy for those cancers might also be enhanced by drugs that disrupt ABCC4-MPP1.
