Antibiotics in early life and childhood pre-B-ALL. Reasons to analyze a possible new piece in the puzzle

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer with precursor B-cell ALL (pB-ALL) accounting for ~ 85% of the cases. Childhood pB-ALL development is influenced by genetic susceptibility and host immune responses. The role of the intestinal microbiome in leukemogenesis is gaining increasing attention since Vicente-Dueñas' seminal work demonstrated that the gut microbiome is distinct in mice genetically predisposed to ALL and that the alteration of this microbiome by antibiotics is able to trigger pB-ALL in Pax5 heterozygous mice in the absence of infectious stimuli. In this review we provide an overview on novel insights on the role of the microbiome in normal and preleukemic hematopoiesis, inflammation, the effect of dysbiosis on hematopoietic stem cells and the emerging importance of the innate immune responses in the conversion from preleukemic to leukemic state in childhood ALL. Since antibiotics, which represent one of the most widely used medical interventions, alter the gut microbial composition and can cause a state of dysbiosis, this raises exciting epidemiological questions regarding the implications for antibiotic use in early life, especially in infants with a a preleukemic "first hit". Sheading light through a rigorous study on this piece of the puzzle may have broad implications for clinical practice.

Keywords: Antibiotics; Childhood acute lymphoblastic leukemia; Inflammation; Inherited susceptibility; Innate immune response; Leukemia microenvironment; Microbiome.

Fig. 1

Innate immune cells undergo epigenetic modifications following infections or vaccination, which provide them with a memory, which subsequently modulates their response to a second infection exposure later in life (“trained immunity”). Delayed recurrent infections cause a decline in antitumor immuno-surveillance and the maturation arrest of B-cells secondary to glucocorticoid release in response to infection. The release of pro-inflammatory (Th1) cytokines promotes cell survival and a hypermutable state, whereas the release of Th2 cytokines and IL-7 stimulates immature B-cell proliferation, including preleukemic cells. The putative pediatric pB-ALL initiating niche shows gene expression signatures of bone marrow mesenchymal stem cell (MSC) with pro-inflammatory and suppressor niches. The differentiation of human classical monocytes towards the non-classical monocyte lineage is enhanced by the presence of human B-ALL. Acute leukemia interacts with the vascular endothelium leading to increased vascular permeability and non-classical monocytes emerge in response to leukemia-induced inflammation. Hematopoietic stem cells (HSC) express Toll-like receptors (TLRs), which are able to recognize microbial components and initiate innate immune responses. Bacterial lipopolysaccharide (LPS) binds the TLR4/Myd88 receptor complex on HSC and stimulates myeloid differentiation pathways, providing a means for rapid replenishment of the innate immune system during infection. The microbiome regulates neutrophil ageing and is required to balance hematopoiesis. A state of dysbiosis with persistent low plasmatic LPS leves can induce loss of lymphoid differentiation in HSC and a myeloid shift. One may hypothesize that whereas a healthy, species-rich microbiome balances normal hematopoiesis, the depletion of the microbiome by antibiotics followed by a state of dysbiosis, with persistently low plasmatic LPS levels may contribute to a lymphoid-myeloid shift and the generation of a myeloid inflammatory microenvironment, predisposing pre-leukemic cells to progression to overt pB-ALL