Thirdhand Smoke As a Risk Factor for Pediatric Lymphoblastic Leukemia: Accelerated Leukemia in Female Pax5-P80R Mice

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. The development of ALL involves genetic and epigenetic processes, but how these factors are influenced by prenatal and early life exposures is poorly understood.

Epidemiologic studies of tobacco smoke and childhood leukemia have suggested that smoking may increase risk for some children. Thirdhand smoke (THS) has gained wide attention in recent years as a newly described health risk. THS includes tobacco smoke residues in indoor environments that remain long after smoking has ended, and which then react and/or re-emit from materials and/or from surfaces. Infants can be exposed to THS through directly contacting these surfaces as well as exposure to house dust and indoor air. We hypothesize that THS exposure interacts with underlying genetics to place children at risk for the development of ALL.

We performed a pilot study to assess whether THS exposure can accelerate the development of ALL in C57BL/6J mice expressing a Pax5^P80R allele, a genetic change that efficiently initiates leukemia. Mutations to the PAX5 locus are common abnormalities in human pediatric ALL. These mice therefore provide a model of the situation in humans in which a child acquires a mutation that, in combination with additional lesions, leads to leukemia. A cohort of Pax5^WT/P80R animals was established that resulted from exposure of sires to THS for at least 6 weeks, mated with dams exposed at the onset of mating, and with exposure of pups continued until weaning at 3 weeks of age.

Results: In our experimental design, we pre-planned to analyze survival in all pups, in female pups, and in male pups. Pooled analysis with all female and male mice showed the median time to leukemia/lymphoma in Sham-exposed mice was 151 d. vs.140.5 d. for THS-exposed mice (p>0.1). Analysis of females showed the median time to leukemia/lymphoma in Sham-exposed mice was 156 d. vs. 134 d. for THS-exposed mice (p=0.02 by log-rank test). Analysis of males showed the median time to leukemia lymphoma in Sham-exposed mice was 143.5 d. vs. 151 d. for THS-exposed mice (p>0.1 by log-rank test). The results described above indicate that THS can influence the initiation of leukemia in Pax5^P80R mice and can promote leukemia, which is remarkably specific for female mice.

Conclusion: Our results unexpectedly showed a sex-bias in the leukemia-promoting effect of THS. Exposure of Pax5^WT/P80R animals to THS provides a model for testing hypotheses regarding how THS and sex may interact in leukemogenesis.

Kogan:Spark Therapeutics: Consultancy; Daiichi Sankyo: Consultancy.