THE MECHANISM OF BENZENE-INDUCED LEUKEMIA - A HYPOTHESIS AND SPECULATIONS ON THE CAUSES OF LEUKEMIA

An overall hypothesis for benzene-induced leukemia is proposed. Key co mponents of the hypothesis include a) activation of benzene in the liv er to phenolic metabolites; b) transport of these metabolites to the b one marrow and conversion to semiquinone radicals and quinones via per oxidase enzymes, c) generation of active oxygen species via redox cycl ing; d) damage to tubulin, histone proteins, topoisomerase II, other D NA associated proteins, and DNA itself; and e) consequent damage inclu ding DNA strand breakage, mitotic recombination, chromosome translocat ions, and aneuploidy. If these effects take place in stem or early pro genitor cells a leukemic clone with selective advantage to grow may ar ise, as a result of protooncogene activation, gene fusion, and suppres sor gene inactivation. Epigenetic effects of benzene metabolites on th e bone marrow stroma, and perhaps the stem cell itself, may then foste r development and survival of the leukemic clone. Evidence for this hy pothesis is mounting with the recent demonstration that benzene induce s gene-duplicating mutations in human bone marrow and chromosome-speci fic aneuploidy and translocations in peripheral blood cells. If this h ypothesis is correct, it also potentially implicates phenolic and quin onoid compounds in the induction of ''spontaneous'' leukemia in man.