Risk Factors for Childhood Leukemia: Radiation and Beyond

Abstract

Childhood leukemia (CL) is undoubtedly caused by a multifactorial process with genetic as well as environmental factors playing a role. But in spite of several efforts in a variety of scientific fields, the causes of the disease and the interplay of possible risk factors are still poorly understood. To push forward the research on the causes of CL, the German Federal Office for Radiation Protection has been organizing recurring international workshops since 2008 every two to three years. In November 2019 the 6th International Workshop on the Causes of CL was held in Freising and brought together experts from diverse disciplines. The workshop was divided into two main parts focusing on genetic and environmental risk factors, respectively. Two additional special sessions addressed the influence of natural background radiation on the risk of CL and the progress in the development of mouse models used for experimental studies on acute lymphoblastic leukemia, the most common form of leukemia worldwide. The workshop presentations highlighted the role of infections as environmental risk factor for CL, specifically for acute lymphoblastic leukemia. Major support comes from two mouse models, the Pax5+/− and Sca1-ETV6-RUNX1 mouse model, one of the major achievements made in the last years. Mice of both predisposed models only develop leukemia when exposed to common infections. These results emphasize the impact of gene-environment-interactions on the development of CL and warrant further investigation of such interactions — especially because genetic predisposition is detected with increasing frequency in CL. This article summarizes the workshop presentations and discusses the results in the context of the international literature.

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 ].…”

“…For childhood B cell precursor ALL, various hypotheses have been proposed as causal factors in disease progression after birth, including population mixing, infection and delayed infection [ 149 , 150 , 151 , 152 ]. In the delayed infection hypothesis, the acquisition of additional mutations, such as those that alter RAG-mediated copy number of cell cycle or B lymphoid lineage differentiation genes [ 153 , 154 ], are proposed to be driven by infections by common pathogens rather than by any specific pathogen [ 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ]. These include upper respiratory and gastrointestinal infections (viral, bacterial, fungal, and potentially including SARS-CoV2 and related viruses), which induce an abnormal immune response or chronic inflammation [ 124 , 141 , 143 , 155 ].…”

In Utero Development and Immunosurveillance of B Cell Acute Lymphoblastic Leukemia

“…External factors such as radiation, smoking, and infections, amongst others, can play a role in utero or postnatally. Radiation and smoking have already been reviewed elsewhere [ 91 , 92 ], associating high doses of ionizing radiation with ALL development and paternal smoking preconception and during pregnancy with an elevated risk for ALL.…”