Identifying therapeutic targets for aggressive blood cancers

A new study published today in the journal Genes & Development reveals a gene that normally suppresses tumor formation but is reprogrammed at the onset of acute promyelocytic leukemia (APL)

The discovery paves the way for the development of drugs that boost the expression of this gene in the early stages of cancer development, blocking it before the disease becomes unmanageable

APL occurs because of a chromosomal translocation, where one chromosome breaks and a part of it reattaches to another chromosome

Treatment of APL includes drugs such as all-trans retinoic acid (ATRA), which lead to remission in 90% of cases

Although chromosomal translocations are important in triggering the disease, little is known about how PML-RARα alters the genome structure of cells

They found that PML-RARα triggers a series of changes that lead to changes in chromosomal structural support and repression of transcription, as well as changes in chromosomal compartments that can "turn on" or "turn off" specific regions of the genome

One of the genes most affected by these changes in the early stages is KLF4, which encodes a protein that binds to DNA to control the rate at which genetic information is transcribed, also known as a transcription factor

"In acute promyelocytic leukemia, KLF4 overexpression acts as a tumor suppressor

The method, developed in Luciano Di Croce's lab at CRG, can also be used to study changes in the genome structure of other types of cancer, which, according to the authors, could reveal other possible yet-to-be-discovered therapeutic targets