Acute myeloid leukemia (AML) is an aggressive blood cancer that causes uncontrolled accumulation of white blood cells. Researchers at Baylor College of Medicine and collaborating institutions report they have uncovered a new vulnerability of this cancer that can be targeted with a class of experimental drugs.
The findings are published in Cancer Research in an article titled, “SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia.”
The researchers show that drugs inhibiting SWI/SNF induce a therapeutic response in AML cell lines, animal models, and human AML samples. In animals, this strategy caused rapid regression of the cancer within days.
“Our project set out to better understand a vulnerability in AML that could be exploited to treat the disease,” said corresponding author, H. Courtney Hodges, PhD, assistant professor of molecular and cellular biology and member of the Dan L. Duncan Comprehensive Cancer Center at Baylor.
The researchers also discovered important mechanisms related to SWI/SNF. “We found that AML cells hijack a gene regulation program that involves SWI/SNF and another protein called PU.1. This program is normally used to make healthy white blood cells,” said first author Courtney Chambers, a graduate student in the Hodges lab.
“Think of each cell’s DNA as a huge labyrinth with many doors behind which are genes that contain instructions on how to make proteins,” Hodges explained. “Most of these doors do not lead to genes of interest to a blood cell, so these cells need a way to know which doors lead to the specific genes they need. Here is where PU.1 plays a role.”
“We found that PU.1 flags the doors that lead to genes of interest to certain blood cells,” said Chambers. “In the case of AML cells, these flags mark genes that promote growth of AML, called oncogenes. PU.1 tags the doors but cannot open them, so SWI/SNF comes along.”
“It was very exciting to see how effective SWI/SNF inhibitors were to treat AML in animal models,” Chambers said. “The effect was much more profound than we had expected.”
The researchers are continuing their research into similar vulnerabilities of AML and other cancers.