High birth weight, genetic susceptibility, and childhood B cell leukemia

B-cell Acute lymphoblastic leukemia (B-ALL) is the most common type of childhood cancer and it remains a major cause of death in children aged 2-6 years in high-income countries. The majority of B-ALL are caused by the combination of prenatal genetic predispositions (e.g. Pax5 mutations) and oncogenic events occurring after birth (e.g. Jak3 mutations). High birth weight is an established risk factor for childhood leukaemia and indicates the importance of intrauterine growth regulation in the aetiology of this disease. Supporting this association, also maternal diabetes has been described as a risk of childhood B-ALL in the offspring. Our research group has previously identified the role of other factors, like are the exposure to infection and gut microbiome dysbiosis, in the development of B-ALL in the context of a Pax5+/- genetic susceptibility. Consequently, the overall objective of this application is to decipher the link between high birth weight and B-ALL in the context of a Pax5+/- genetic susceptibility. In this work, we will Aim 1 to study the role of fetal overweight in the conversion of Pax5+/- preleukemic clones, Aim 2 to study the interaction between the secondary acquired mutations in Jak3 and Pax5 genetic susceptibility, and in Aim 3 we will validate the preclinical results of the two previous objectives in primary samples of children with B-ALL. In summary, we will seed light in the biological mechanism underlying the positive association that has been reported between accelerated fetal growth and risk of childhood ALL and set the starting point for the development of novel and innovative strategies for leukemia prevention.