The role of microenvironment in the initiation and evolution of B-cell precursor acute lymphoblastic leukemia.

B cell precursor acute lymphoblastic leukemia (BCP-ALL) is a malignant disorder of immature B lineage immune progenitors and is the commonest cancer in children. Despite treatment advances it remains a leading cause of death in childhood and response rates in adults remain poor. A preleukemic state predisposing children to BCP-ALL frequently arises in utero, with an incidence far higher than that of transformed leukemia, offering the potential for early intervention to prevent disease. Understanding the natural history of this disease requires an appreciation of how cell-extrinsic pressures, including microenvironment, immune surveillance and chemotherapy direct cell-intrinsic genetic and epigenetic evolution. In this review, we outline how microenvironmental factors interact with BCP-ALL at different stages of tumorigenesis and highlight emerging therapeutic avenues.

Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain Salmonella.

Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ-/- mice succumb rapidly to STm infections, T-bet-/- mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STm-infected IFN-γ-/- and T-bet-/- mice. In IFN-γ-/- mice, there is deficient granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination of bacteria throughout the organs, and rapid death. The provision of a source of IFN-γ reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-γ. T-bet-/- mice induce significant levels of IFN-γ- after challenge. Moreover, T-bet-/- mice have augmented IL-17 and neutrophil numbers, and neutralizing IL-17 reduces the neutrophilia but does not affect numbers of bacteria detected. Surprisingly, T-bet-/- mice exhibit surprisingly wild-type-like immune cell organization postinfection, including extensive iNOS+ granuloma formation. In wild-type mice, most bacteria are within iNOS+ granulomas, but in T-bet-/- mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-γ-dependent iNOS+ granulomas and prevent dissemination.