Genome organization plays a crucial role in transcription. However, how transcription factors (TFs) rewire the structure of the genome to maintain the programs that lead to oncogenic transformation remains poorly understood. Now, a new study in mice models demonstrates that a gene that normally suppresses the formation of tumors but is reprogrammed at the onset of acute promyelocytic leukemia (APL), an aggressive type of blood cancer. The findings pave the way for the development of drugs that boost the expression of the gene at the earliest stages of cancer formation.
The findings are published in the journal Genes & Development in a paper titled, “In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation,” led by researchers at the Centre for Genomic Regulation (CRG) and the Centro Nacional de Análisis Genómico (CNAG-CRG) in Barcelona, and the European Institute of Oncology in Milan.
“APL is a fatal subtype of leukemia driven by a chromosomal translocation between the promyelocytic leukemia (PML) and retinoic acid receptor α (RARα) genes,” the researchers wrote. “We used primary hematopoietic stem and progenitor cells (HSPCs) and leukemic blasts that express the fusion protein PML-RARα as a paradigm to temporally dissect the dynamic changes in the epigenome, transcriptome, and genome architecture induced during oncogenic transformation.”
APL occurs because of chromosomal translocations, in which a chromosome breaks and a portion of it reattaches 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.
One of the genes most affected by these changes at an early stage is KLF4, which codes for a protein that binds to DNA to control the rate of transcription of genetic information, also known as a transcription factor. KLF4 activity is inactivated during the progression of APL. The researchers found that when cells were manipulated to overexpress KLF4, it suppressed the self-renewal traits of cancerous 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 finding opens a new avenue of treatment to target this aggressive disease alongside existing treatments. In follow up studies, we have observed that combination of ATRA with KLF4 overexpression can suppress the cancerous traits mediated by PML-RARa, suggesting a potential therapy for non-responsive or relapsed patients that could be spun off from this work,” said Glòria Mas Martin,PhD, first author of the study and previously a postdoctoral researcher at the CRG.
The findings pave the way for the development of drugs that boost the expression of the gene at the earliest stages of cancer formation, intercepting the disease before it becomes uncontrollable.