L’implication de la peptide-déformylase (PDF) dans la leucémie aiguë lymphoblastique de l’enfant
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, representing 25% of all pediatric tumors. With the current therapies the survival rate is about 90%. However, the remaining patients who do not respond to current treatments still represent the principal cause of mortality related to children’s cancer. To deepen our knowledge on the causes of this disease and to understand the underlying genetic architecture of ALL, we performed a depth study of childhood ALL by characterizing mutations that can drive to leukemogenesis, called driver mutations. The use of high throughput sequencing on a cohort of 389 ALL pre-B pediatric patients led us to identify somatic mutations. Several of these mutations had strong predicted functional impact and were thus considered as putative driver mutations of leukemia. One of these mutations, the non-sense somatic mutation c.t697a on the PDF (peptide deformylase, mitochondrial) gene was shared by three patients. Our research hypothesis is that this mutation is a driver of leukemogenesis. In order to determine the driver potential of the new recurrent mutation c.t697a in PDF, we evaluated its effect in leukemic cells by measuring metabolic activity, apoptosis, and cellular proliferation. It was found that this mutation, when overexpressed in leukemic cells, led to a decrease in ATP production and an increase in apoptosis. Thus, the c.t697a mutation in the PDF gene is not a driver mutation of leukemia. Identification of novel driver mutations will further increase our understanding of the ALL etiology and eventually allow personalized approaches for the management of children attained by this disease.
Mutations drivers Pediatric cancer Acute lymphoblastic leukemia Driver mutations Functional validation