JAX Team Restores Silenced Genes in AML

A team from The Jackson Laboratory (JAX) discovered that a crucial tumor-suppressor gene in acute myeloid leukemia (AML) gets switched off through epigenetic silencing rather than DNA mutations. Their study, published in Science Translational Medicine, demonstrates how to reactivate this gene, offering a potential alternative to harsh chemotherapy while revealing new ways to study gene silencing across diseases.

"If we can identify which genes have been silenced and understand how to turn them back on, that could open up entirely new therapeutic possibilities," said study leader Eric Wang. "Instead of only trying to kill these cells, we may be able to restore the mechanisms that normally keep them under control."

Tumor-suppressor genes normally prevent cells from turning cancerous. In AML and similar diseases, cancer cells silence these genes epigenetically—altering their activity without changing the DNA sequence itself. Standard DNA sequencing overlooks these changes since it only detects mutations.

"Clinicians design treatments based on DNA sequencing that detects mutations," Wang explained. "But they don't have any other method to detect epigenetic mechanisms that are also associated with really poor outcomes and cannot be sequenced."

To address this gap, Wang's group invented FISHnCRISP, merging fluorescent imaging with CRISPR technology to map gene activity inside individual cells. The tool pinpointed ZBTB7A, a tumor suppressor silenced in AML.

"Most drugs right now target the genes that are upregulated in tumor cells, but sometimes it's very hard to find a therapeutic for that. Instead, we developed this CRISPR-based screen to identify what upregulates tumor-suppressor genes to kill off the tumor," Wang noted.

AML cells generate an elongated regulatory tail on ZBTB7A that draws in the protein ZFP36L2, dampening its expression. The KDM4 enzyme family further silences the gene by altering DNA packaging. Testing patient-derived AML cells in mice, the researchers found blocking KDM4 reactivated ZBTB7A, shrinking leukemia while preserving normal blood cell production.

"There are drug candidates out there to inhibit KDM4, and in our study we just repurposed one of them to treat AML cells," Wang said. "We won't know unless we test it in clinical trials, but this approach could be better than chemotherapy, because we showed it's not toxic at all to normal blood cells."

AML's poor prognosis stems partly from immature leukemia cells that resist differentiation into mature forms. Restoring ZBTB7A nudged these cells toward white blood cell maturity, slowing growth and promoting death.

"We demonstrated that downregulating ZBTB7A causes this hyper inflammatory state that promotes cancer growth," Wang said. "Now, we're proposing this epigenetic approach to force AML cells to differentiate into white blood cells that eventually undergo cell death."

The team eyes KDM4 inhibitors already in solid tumor trials for faster AML testing. "We could potentially translate our research into an early phase clinical trial more readily than developing a whole new compound from scratch," Wang concluded.