Luciano Di Croce & Marc Martí-Renom

Centre de Regulació Genòmica (CRG)

Acute Promyelocytic Leukaemia (APL) is an aggressive type of blood cancer that is responsible for 5- 15% of all types of leukaemia, which 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 (RAR?) genes. The expression a new protein – PML/RAR? – in hematopoietic stem cells blocks their differentiation. Eventually, the bone marrow fills up with abnormal white blood cells known as promyelocytes that lead to a shortage of other types of blood cells and prevent normal blood production.

We found that PML-RAR? initiates a series of alterations that result in specific changes chromatin organization and the repression of transcription.

One of the genes most affected by these changes at an early stage was 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 was inactivated during the progression of APL. We found that, when cells were manipulated to overexpress Klf4 many traits of cancerous cells were reversed.

The findings pave the way for the development of drugs that boost the reactivation of the genes repressed at the earliest stages of cancer formation (such as Klf4), intercepting the disease before it becomes uncontrollable.

The method, developed in our laboratory, can also be used to study changes to the genomic architecture of other types of cancer, which could reveal other possible therapeutic targets yet to be discovered.