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.B细胞急性淋巴细胞白血病（B-cell Acute lymphoblastic leukemia, B-ALL）是儿童最常见的癌症类型，在高收入国家中仍是2~6岁儿童死亡的主要诱因。绝大多数B-ALL由产前遗传易感因素（如Pax5突变）与出生后发生的致癌事件（如Jak3突变）共同诱发。高出生体重已被证实为儿童白血病的明确危险因素，这凸显了宫内生长调控在该病病因学中的重要地位。与此关联相印证的是，母体糖尿病也被证实会增加后代罹患儿童B-ALL的风险。我们研究团队此前已在Pax5+/-遗传易感背景下，明确了感染暴露与肠道菌群失调等其他因素在B-ALL发生发展中的作用。本申请的总体目标是阐明Pax5+/-遗传易感背景下高出生体重与B-ALL之间的关联机制。在本研究中，我们将开展三项研究任务：目标1探究胎儿超重在Pax5+/-白血病前克隆转化过程中的作用；目标2研究Jak3继发获得性突变与Pax5遗传易感之间的相互作用；目标3将在儿童B-ALL患者的原代样本中验证前两项研究的临床前结果。综上，本研究将阐明已报道的胎儿生长加速与儿童急性淋巴细胞白血病风险之间正相关关联的潜在生物学机制，并为开发新型白血病预防策略奠定基础。