A new study published today in the journal Genes & Development reveals a gene that normally suppresses tumor formation but is reprogrammed early in acute promyelocytic leukemia (APL), an aggressive type of blood cancer responsible for 5-15% of all types of leukemia.
The findings pave the way for the development of drugs that stimulate gene expression in the early stages of cancer formation, intercepting the disease before it spirals out of control.
APL occurs due to chromosomal translocations, in which a chromosome breaks and part of it attaches to a different chromosome. In APL, this results in a gene fusion event between the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARα) genes. Previously healthy stem cells begin to express a new protein – PML/RARα – which blocks their differentiation. Eventually, the bone marrow fills with abnormal white blood cells called promyelocytes which lead to a shortage of other types of blood cells and prevent normal blood production.
Treatments for APL include drugs such as all-trans-retinoic acid (ATRA), which lead to remission in 90% of cases. However, new therapeutic routes are still needed for patients who do not respond to this treatment, as well as for the large proportion of patients who relapse after a few years.
Despite the importance of chromosomal translocations in disease initiation, little is known about how PML-RARα alters the genomic architecture of cells. Researchers from the Center for Genomic Regulation (CRG) and Centro Nacional de Análisis Genómico (CNAG-CRG) in Barcelona, and the European Institute of Oncology in Milan, used mouse models that closely mimic the progression of the APL in humans to study changes in cells at the onset and progression of disease.
They found that PML-RARα initiates a series of alterations that lead to changes in the structural support of chromosomes and repression of transcription, as well as changes in chromosomal compartments that ‘open’ or ‘close’ access to particular regions of the genome.
One of the genes most affected by these early-stage changes was KLF4, which encodes a protein that binds DNA to control the rate of transcription of genetic information, also known as a transcription factor. Klf4 activity was inactivated during APL progression. The researchers found that when cells were manipulated to overexpress Klf4, it suppressed the self-renewal traits of cancer cells and reversed the effects caused by the actions of PML-RARα.
“Overexpression of Klf4 acts as a tumor suppressor in acute promyelocytic leukemia. Our discovery opens up a new treatment avenue to target this aggressive disease alongside existing treatments. In follow-up studies, we have observed that the combination of the ‘ATRA with Klf4 overexpression may suppress cancer traits mediated by PML-RARa, suggesting a potential therapy for non-responder or relapsed patients that could arise from this work,’ explains Glòria Mas Martin, first author of the study and previously postdoctoral researcher at the CRG.
The method, developed in the laboratory of Luciano Di Croce at the CRG, can also be used to study changes in the genomic architecture of other types of cancer, which the authors believe could reveal other possible therapeutic targets yet to be discovered. . “The steps that trigger cancer are the most interesting because they are the equivalent of the snowball turning into an avalanche. This approach could be used to understand the very early effects of other oncogenic proteins that act as transcriptional repressors, leading to the development of new therapies that target a mechanism before it gets out of hand,” says Luciano Di Croce, research professor at ICREA, lead author of the study and researcher at CRG.
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