Pediatric leukemia: origins, pathogenesis, the role of microenvironment and immunological modulation.

Leukemia remains the most commonly diagnosed pediatric cancer worldwide. Over the last decade, advances in therapy have significantly improved survival rates; however, treatment outcomes are still unsatisfactory for many patients. Further progress requires a comprehensive understanding of disease biology, including the hematopoietic process, mechanisms of leukemia initiation and progression, the genetic mutations involved, and the cell types that constitute the pre-leukemic and leukemic niches and interact with their microenvironment. Particular attention should be paid to the role of inflammation and immune modulation in the development of this childhood malignancy. Hematopoiesis occurs in three waves, and several hematopoietic niches are involved in cell development and maturation. In these locations, primary pre-leukaemic clones arise prenatally, yet only a subset of cases progress to overt leukemia after birth. In most patients, malignant progression is associated with the acquisition of secondary mutations, which may result from inflammation or exposure to specific infectious agents. Microenvironmental factors play a critical role in this process. Cross-talk between niche components and emerging leukaemic cells gradually shapes a microenvironment that favors malignancy. Extensive remodeling of this niche is driven by structural alterations, deregulation of signaling pathways essential for proper cell function and disturbances in the secretion of immunological factors, thereby creating a supportive and protective environment for leukemia progression. A detailed understanding of fetal hematopoiesis in the context of leukemia, and of how immunomodulatory factors and inflammatory mediators influence disease development, is crucial for improving therapeutic efficacy. This review provides an in-depth overview of these phenomena and, in addition to core information on pediatric leukemia, summarizes recent advances in elucidating its origin and pathogenesis, as well as emerging diagnostic and therapeutic approaches.