Towards the prevention of childhood leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer and leading cause of pediatric cancer death. In childhood B-ALL, a mutation (hereditary or de novo) leads to appearance of preleukemic cells that are capable of normal lymphoid differentiation; however, upon acquisition of one or more second hit mutations, these preleukemic cells transform into full-blown leukemic blasts. While identification of the specific events that trigger the malignant evolution of preleukemic cells has remained elusive in humans, it has long been hypothesized that (delayed) exposure to infection promotes an immune response that then spurs the acquisition of additional genetic lesions [1]. Recently, independent studies using different genetically predisposed mice have demonstrated the occurrence of such an infection-triggered leukemogenic mechanism, collectively showing that several types of stress in the immune system can promote clonal evolution of preleukemic cells in a significant proportion of mice [2–4]. Interestingly, the immune stress does not act by selecting a preleukemic clone that already harbors the second hit; on the contrary, the infection acts by promoting acquisition of the second hit itself, therefore leading to full-blown B-ALL [1]. Together, these observations support the idea that by eliminating preleukemic cells, childhood B-ALL might be preventable [1–5]. Nevertheless, it has remained unclear how to target preleukemic cells as a means to prevent the development of B-ALL. To address this question, we took advantage of the Pax5+/− mice [2, 4]. Similar to children who harbor heterzygous germline PAX5 mutations, B-ALL develops in up to 25% of Pax5+/− mice, but only when these animals experience an immune stress, such as exposure to infection [2]. The leukemias that develop in this model acquire various types of second hit mutations which resemble those observed in human B-ALL, including activating mutations affecting the Janus Kinases (JAKs) [2]. We previously observed that pro-B cells in Pax5+/− mice are particularly dependent on the cytokine interleukin-7 (IL-7) for their survival, and that blocking IL-7-induced signaling using the JAK1/2 inhibitor ruxolitnib led to increased cell death in vitro [2]. Based on these findings, we used Pax5+/− mice to explore whether treatment with Editorial