Acute myeloid leukemia following exposure to benzene more closely resembles de novo than therapy related-disease

Benzene (Bz) is widely regarded as a prototype environmental leukemogen and individuals chronically exposed are at risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It is widely assumed that initiation and pathogenesis of AML following Bz exposure (Bz-AML) is similar or identical to therapy-related AML (t-AML), in which clonal cytogenetic abnormalities, including aneuploidy, are initiating events. However, this assumption is not supported by studies reporting actual disease outcomes together with cytogenetic analyses. Here, using clinically relevant cytogenetic, hematologic, and epidemiological methods, we directly show for 722 consecutive AML cases that the pattern of clonal cytogenetic abnormalities encountered in Bz-exposed cases (n=78) more closely resembles de novo-AML than t-AML. The prevalence of aneuploidy in Bz-exposed- and de novo-AML cases was identical (23%), and no significant increases in -5/5q- (RR=0.79) (95% CI: 0.29-2.12) or -7/7q- (RR=1.27) (95% CI: 0.55-2.92) abnormalities were observed between Bz- vs de novo-AML, respectively. Previous studies have suggested a role for autoimmunity in Bz related MDS including immune mediated inflammatory features and positive responses to immunosuppressive therapy which are indistinguishable from those reported in MDS with low risk of progression to AML. These observations are more consistent with an epigenetic model for initiation of Bz-AML in which altered homeostatic regulation in the bone marrow niche, not direct cytogenetic injury, predominates in the initial development of the leukemic stem cell phenotype, a mechanism biologically distinct from previous models of clonal cytogenetic injury. These findings are important for further understanding the biological basis of AML, particularly in environmental and occupational settings. (c) 2013 Wiley Periodicals, Inc.