The double-edged sword of immune stress in leukemic progression. Different types of mutations can cause genetic predisposition to B-ALL in at least 5% of newborns, as they lead to the appearance of PLCs from the earliest stages of embryonic life. In the majority of cases, these PLCs will not evolve to full-blown B-ALL, but exposure to environmental stresses such as infections can alter this benign path. The interplay between the nature of the genetic predisposition, the infectious agent, and the age at the time of exposure can produce opposite results. Indeed, in some cases the immune stress triggered by the infection can cause the destruction of the preleukemic clone and prevent leukemia progression, while in some others, it can trigger the appearance of secondary mutations (2nd hit) leading to BALL development. Figure created with BioRender.com.