(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

development of MDS)and/or AML. It is also clear that AML arising secondary to treatment with
alkylating chemotherapeutic agents is a clinical entity distinct from AML arising de novo, or
primary, which has no readily identifiable cause (Coltman et al., 1990; Park et al., 1996). One
hallmark of this type of secondary leukemia (s-AML) is the involvement of recognizable
cytogenetic lesions, specifically the loss of part or all of chromosomes 7 and/or 5 (Rowley et al.,
1989; 1997; Leone et al., 1999). It has been estimated that cytogenetic lesions involving
chromosomes 7 and/or 5 occur 65–95% of the time in AML arising secondary to alkylating
agents (Johansson et al., 1991). In contrast, deletions of chromosome 5 and/or 7 occur much
less frequently in primary AML (Rowley et al., 1981; Leone et al., 1999). AML cases in workers
occupationally exposed to benzene, where appropriate analysis has been conducted, often
possess the same types of cytogenetic lesions which suggests a shared pathogenic mechanism
(Zhang et al., 2002; Smith, et al., 1998; Zhang et al., 1996; Mitelman et al., 1981; Mitelman et
al., 1978; Mitelman et al., 1984; Golomb et al., 1982; Fagioli et al., 1992; Cuneo et al., 1992;
Narod et al., 1989; Van den Berghe et al., 1979). In a recent comprehensive review, authors
concluded that monosomy 5 and monosomy 7 are the most common cytogenetic abnormalities
observed in benzene induced AML (Zhang et al., 2002).
Recently, clinical studies have revealed that a different form of AML can arise secondary to
treatment with drugs that primarily target topoisomerase II (e.g. epotoside), an enzyme required
for DNA replication (Beaumont et al., 2003; Hoffmann et al., 1995; Anderson et al., 2002;
Pedersen-Bjergaard et al., 2002). The most common cytogenetic abnormality in AML
secondary to agents that target topoisomerase II is 11q23 (Pedersen-Bjergaard et al., 2002; De
Renzo et al., 1999). There have also been examples of chemicals that inhibit topoisomerase II
and do not form cleavable complexes. Bimolane acts in this manner and induces an AML with
characteristics similar to classic topoisomerase poisons, but with a different predominant
cytogenetic lesion (21q22) (Zhang et al., 2002). It has been shown that various benzene
metabolites under appropriate enzymatic conditions can inhibit topoisomerase II and some
investigators believe this may be an important pathway in benzene induced leukemia (Whysner
et al., 2004). It is not clear what role inhibition of topoisomerase II may or may not play in the
development of benzene induced AML (Chen et al., 1995). However, the patterns of cytogenetic
abnormalities typically associated with inhibition of this enzyme have not been observed in
occupationally exposed populations (Zhang et al., 2002).
The presence of specific cytogenetic abnormalities in both benzene and alkylating
chemotherapy induced AML suggests that these lesions are non-random and could play a role
in the pathogenesis of at least some cases of the disease. Monosomy 7 or an interstitial
deletion at 7q- is the most commonly reported cytogenetic abnormality in therapy related AML.
A number of gene loci have been mapped to chromosome 7, but their function in hematopoiesis
and leukemogenesis remain largely unknown (Luna-Fineman et al., 1995). Additionally, 7- /7q-
are often seen in sub-clones of the leukemia or as evolutionary events during disease
progression (Pedersen-Bjergaard et al., 2002). In contrast, an interstitial deletion in
chromosome 5 (5q31-) is the earliest cytogenetic abnormality that has been detected in therapy
related AML (Le Beau et al., 1986b ; Le Beau et al., 1986a; Van den Berghe et al., 1985).
There are a variety of important hematopoietic genes mapped to this region of the chromosome
including hematopoietic cytokines/growth factors (GM-CSF, IL-3, IL-4, IL-5) and CD14, a
myeloid specific surface molecule (Rowley and Le Beau, 1989). Additionally, the early growth
response 1 (EGR-1) gene is located in this region of chromosome 5 and is required for
monocyte-macrophage differentiation (Rowley and Le Beau, 1989). It is currently not clear how
specific deletions on chromosome 5 or 7 could result in a dysregulated hematopoietic
environment in the bone marrow or the development of a transformed leukemic clone
Benzene VCCEP Submission
March 2006
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