Abstract

Simple SummaryThe childhood obesity epidemic is impacting tens of millions of children globally. While obesity causes several cancers in adults, its potential role in causing pediatric cancers remains unclear. In this review, we assess the potential contribution of obesity to the development of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. We review the possible mechanisms by which the adipose tissue attracts and protects leukemia cells and how it interferes with the actions of chemotherapies used in ALL treatment. We also examine adipose tissue-secreted molecules and fuels that may support leukemia development. While there are no current definite causal links between obesity and ALL, there are plausible mechanisms that need further investigation to explore the impact of obesity on causing ALL and on impacting treatment outcomes.Childhood obesity is a growing epidemic with numerous global health implications. Over the past few years, novel insights have emerged about the contribution of adult obesity to cancer risk, but the evidence base is far more limited in children. While pediatric patients with acute lymphoblastic leukemia (ALL) are at risk of obesity, it is unclear if there are potential causal mechanisms by which obesity leads to ALL development. This review explores the endocrine, metabolic and immune dysregulation triggered by obesity and its potential role in pediatric ALL’s genesis. We describe possible mechanisms, including adipose tissue attraction and protection of lymphoblasts, and their impact on ALL chemotherapies’ pharmacokinetics. We also explore the potential contribution of cytokines, growth factors, natural killer cells and adipose stem cells to ALL initiation and propagation. While there are no current definite causal links between obesity and ALL, critical questions persist as to whether the adipose tissue microenvironment and endocrine actions can play a causal role in childhood ALL, and there is a need for more research to address these questions.

Highlights

  • The rates of childhood obesity have started to plateau in high-income countries, yet they continue to rise in low- and middle-income countries [1]

  • While some studies suggested that age, sex, cranial irradiation (CRT) and steroids may play a role in obesity development in acute lymphoblastic leukemia (ALL) survivors [35,37,40,41,53,54,55], a recent meta-analysis of 20 studies (n = 1742) demonstrated that the mean body mass index (BMI) z-score was 0.83

  • This signaling includes the overexpression of phosphatidylinositol 3-kinase (PI3K)/Akt and STAT3 in lymphoblasts that is associated with chemotherapy resistance and poor prognosis [96,128,129,130,131,132]

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Summary

A Review

Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, ON L8N 3Z5, Canada. De Groote School of Medicine, McMaster University, Hamilton, ON L8S4L8, Canada. Division of Pediatric Hematology/Oncology, McMaster Children’s Hospital, Hamilton, ON L8N 3Z5, Canada. While obesity causes several cancers in adults, its potential role in causing pediatric cancers remains unclear. We assess the potential contribution of obesity to the development of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. We review the possible mechanisms by which the adipose tissue attracts and protects leukemia cells and how it interferes with the actions of chemotherapies used in ALL treatment. We examine adipose tissue-secreted molecules and fuels that may support leukemia development. While there are no current definite causal links between obesity and ALL, there are plausible mechanisms that need further investigation to explore the impact of obesity on causing ALL and on impacting treatment outcomes

Introduction
Obesity at Initial ALL Diagnosis
Findings
18–20 Gy CRT
Birth Weight and ALL
Obesity is Common Among Survivors of Childhood ALL
The Association of Obesity with Relapse Risk and Mortality in ALL
Potential Mechanisms by Which Obesity May Contribute to ALL Pathogenesis
White Adipose Tissue is Far More Than a Passive Calorie Sink in Obesity
Adipocytes Interference in Pharmacokinetics of ALL Chemotherapies
Cytokines
Natural Killer Cell Dysregulation
Adipose-Derived Stem Cells
Targeted Therapy for Obesity-Associated Acute Lymphoblastic Leukemia
Conclusions
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