Gut microbiome in pediatric acute leukemia: from predisposition to cure

Abstract

The gut microbiome (GM) has emerged as a key factor in the genesis and progression of many diseases. The intestinal bacterial composition is also able to influence treatment-related side effects and even efficacy of oncological therapies. Acute leukemia (AL) is the most common cancer among children and the most frequent cause of death from cancer during childhood. Outcome has improved considerably over the past four decades, with the current long-term survival for acute lymphoblastic leukemia being approximately 90%. However, several acute toxicities and long-term sequela are associated with the multimodal therapy-protocols applied in these patients. Specific GM configurations could contribute in the multistep developmental hypothesis for leukemogenesis. Moreover, GM alterations occur during the AL therapeutic course and are associated with treatment-related complications, especially during hematopoietic stem cell transplantation. The GM perturbation could last even after the removal of microbiome-modifying factors, like antibiotics, chemotherapeutic drugs or allo-immune reactions, contributing to several health-related issues in AL survivors. The aim of this paper is to provide a comprehensive review of the chronological changes of GM in children with AL, from predisposition to cure. The underpinning biological processes and the potential interventions to modulate the GM towards a potentially health-promoting configuration are also highlighted.

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…Other prenatal translocations/rearrangements reported in ALL subtypes include, although not exclusively, BCR/ABL1 and TCF3/PBX1 gene fusions and KMT2A rearrangements, including the t(4;11)/ KMT2A/AFF1 fusion gene [ 138 , 143 ]. Similar “preleukemic” changes have been detected at birth in the blood of healthy children, who do not subsequently develop ALL [ 6 , 121 , 122 , 124 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ]. Notably, about 1% to 5% of newborns are reported to carry ETV6-RUNX1 gene fusions in approximately 1 in 10,000 B lymphoid lineage cells (although this varies considerably amongst different studies) without overt B cell precursor ALL developing in the vast majority of these children, and with predisposing factors for development of B cell precursor ALL post-natally, including environmental factors and additional mutations [ 6 , 121 , 122 , 124 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ].…”

“…Similar “preleukemic” changes have been detected at birth in the blood of healthy children, who do not subsequently develop ALL [ 6 , 121 , 122 , 124 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ]. Notably, about 1% to 5% of newborns are reported to carry ETV6-RUNX1 gene fusions in approximately 1 in 10,000 B lymphoid lineage cells (although this varies considerably amongst different studies) without overt B cell precursor ALL developing in the vast majority of these children, and with predisposing factors for development of B cell precursor ALL post-natally, including environmental factors and additional mutations [ 6 , 121 , 122 , 124 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ]. The second hit is accompanied by independent mutations and subclonal evolution leading to B cell precursor ALL occurring post-natally (at least for the <14-year age group) [ 6 , 121 , 124 , 143 ].…”

“…Because of its prevalence compared to T ALL and AML, there has been a particular interest in understanding the origin and development of pediatric B cell precursor ALL. Risk factors have recently been reviewed in detail elsewhere [ 133 , 141 , 142 , 143 ]. The two-hit model for the development of childhood B cell precursor ALL proposes that an initiating preleukemic event or first hit (e.g., high hyperdiploidy or ETV6/RUNX1 gene fusion) occurs in utero [ 6 , 115 ].…”

Clinical Impact of Nutritional Status and Sarcopenia in Pediatric Patients with Bone and Soft Tissue Sarcomas: A Pilot Retrospective Study (SarcoPed)

“…However, Rayar et al conducted their studies among children with leukemia during the induction treatment when infections are very frequent due to the intensity of the treatment to leukemia itself, which compromises the immune system [45]. Moreover, during treatment, children with leukemia undergo a modification of the gut microbiome, which can affect the nutritional status of the patients, causing an increase in infectious episodes [51]. In soft tissue and bone sarcomas, the treatment has a decisively lower myeloablative effect compared to the induction phase of leukemia with a consequent lower incidence of infectious episodes.…”

Human Microbiome in Children, at the Crossroad of Social Determinants of Health and Personalized Medicine

“…Hence, the idea of the bidirectionality of social and host–microorganism interactions in health should be integrated into research and clinical perspectives from today. In addition to the possible therapeutic implications, some of them already mentioned, modification of the microbiota in childhood has been postulated to be key in the prevention of infections [ 31 ], allergy [ 32 ], asthma [ 33 ], or even cancer in childhood [ 34 , 35 , 36 ]. Therefore, the inclusion of children in clinical trials evaluating dietary modifications and their impact on various diseases and overall health should be prioritized.…”