Aberrations in chromosomes associated with lymphoma and therapy‐related leukemia in benzene‐exposed workers

Abstract

Epidemiological studies show that benzene exposure is associated with an increased incidence of leukemia and perhaps lymphoma. Chromosomal rearrangements are common in these hematopoietic diseases. Translocation t(14;18), the long-arm deletion of chromosome 6 [del(6q)], and trisomy 12 are frequently observed in lymphoma patients. Rearrangements of the MLL gene located on chromosome 11q23, such as t(4;11) and t(6;11), are common in therapy-related leukemias resulting from treatment with topoisomerase II inhibiting drugs. To examine numerical and structural changes in these chromosomes (2, 4, 6, 11, 12, 14, and 18), fluorescence in situ hybridization (FISH) was employed on metaphase spreads from workers exposed to benzene (n = 43) and matched controls (n = 44) from Shanghai, China. Aneuploidy (both monosomy and trisomy) of all seven chromosomes was increased by benzene exposure. Benzene also induced del(6q) in a dose-dependent manner (P(trend) = 0.0002). Interestingly, translocations between chromosomes 14 and 18, t(14;18), known to be associated with follicular non-Hodgkin lymphoma, were increased in the highly exposed workers (P < 0.001). On the other hand, translocations between chromosome 11 and other partner chromosomes that are found in therapy-induced leukemias were not increased. These data add weight to the notion that benzene can induce t(14;18) and del(6q) found in lymphoma, but do not support the idea that benzene induces t(4;11) or t(6;11). However, they do not rule out the possibility that other rearrangements of the MLL gene at chromosome 11q23 may be induced by benzene.

Chromosome Translocations in Workers Exposed to Benzene

“…We recently reported increased t(14;18) translocation in highly exposed workers as measured by FISH ( 20 ), which is contradictory to our current fi ndings by real-time PCR. The discrepancy may be explained by the different target cell populations and differential sensitivities of the two assays.…”

“…We previously reported increased levels of t(8;21) by FISH, in workers highly exposed to benzene, and confi rmed the presence of the translocation in one individual by reverse transcription PCR ( 19 ). We also recently reported the detection of t(14;18) by FISH in 4/22 individuals highly exposed to benzene but not in controls (N = 44) or in lower-exposed workers (N = 21) ( 20 ). However, lack of DNA of suitable quality precluded confi rmation of t(14;18) by qPCR.…”

Avaliação citogenética e molecular de trabalhadores intoxicados pelo benzeno

“…O polimorfismo no gene MPO também pode atuar como um cofator na suscetibilidade para a leucemia etiologicamente associada à exposição ao benzeno, pelas alterações que este polimorfismo acarreta na atividade da enzima, afetando assim o metabolismo do benzeno no organismo, com a formação de adutos no DNA (Zhang et al, 2007).…”

“…A mieloperoxidase, enzima responsável pela transformação dos metabólitos intermediários do benzeno em quinonas tóxicas, pode alterar também a formação de adutos de DNA e proteínas, além da produção de espécies reativas de oxigênio (Zhang et al, 2007). Assim como, a detoxificação das quinonas pode ocorrer via NQO1 ou via enzimas da fase II de metabolização de xenobióticos como as GSTs, resultando em produtos menos tóxicos como as diidroquinonas (Ross et al, 2000).…”

“…A frequência do alelo A no gene MPO varia em cada população, tendo sido descrita em 23,4% dos Caucasianos e 14,4% dos asiáticos (Kiyohara et al, 2005). O genótipo variante de MPO 463 G > A tem sido associado ao risco reduzido de se desenvolver leucemia aguda, capacidade que é frequentemente atribuída à ativação diminuída dos carcinógenos por esta variante (Zhang et al, 2007). Na presente investigação, não foram encontradas diferenças entre os grupos avaliados.…”