Establishment of a zebrafish hematological disease model induced by 1,4-benzoquinone

Abstract

Benzene exposure is associated with various hematological disorders, in particular leukemia. The reactive metabolite of benzene, 1,4-benzoquinone (BQ), generated in bone marrow, is suggested to be a key molecule in mediating benzene-induced hematotoxicity and carcinogenicity. However, its pathogenic role remains largely unknown due to a lack of suitable vertebrate whole-organism models. Here, we present an in vivo study to reveal the effect of BQ exposure on hematotoxicity in zebrafish. From embryonic stages to adulthood, BQ exposure suppressed erythroid and lymphoid hematopoiesis but led to abnormal accumulation of myeloid cells and precursors, which resembles benzene-induced cytopenia and myeloid dysplasia in humans. This myeloid expansion is caused by granulocyte, but not macrophage, lineage, emphasizing the significant role of lineage specificity in BQ-mediated hematopoietic toxicity. Analysis of the c-myb (also known as myb ) - deficient mutant cmyb hkz3 revealed that BQ induced neutrophilia in a c-myb -dependent manner, demonstrating that c-myb is a key intrinsic mediator of BQ hematotoxicity. Our study reveals that BQ causes lineage-specific hematotoxicity in zebrafish from embryonic stages to adulthood. Since c-myb is indispensable for BQ to induce neutrophilia, c-myb could serve as a potential drug target for reversing BQ hematotoxicity.

Blocking exosomal secretion aggravates 1,4‐benzoquinone‐induced mitochondrial fission activated by the AMPK/MFF/Drp1 pathway in HL‐60 cells

“…Although many countries have established the occupational exposure limit for benzene to reduce the harm mediated by it, exposure to benzene concentrations below the USA occupational standard of 1 part per million can cause hematotoxic effects such as reduced erythrocytes, leucocytes, and thrombocytes (Lan et al, 2004; Schiffman et al, 2018). The benzene metabolite, 1, 4‐benzoquinone (1,4‐BQ), is produced in the bone marrow and considered to be one of the major substances mediating hematotoxicity (Zhang et al, 2019). Studies have found that 1,4‐BQ affects mitochondria function, ultimately leads to reactive oxygen species (ROS)‐dependent cell apoptosis (Das et al, 2010; Sun et al, 2018).…”

“…erythrocytes, leucocytes, and thrombocytes (Lan et al, 2004;Schiffman et al, 2018). The benzene metabolite, 1, 4-benzoquinone (1,, is produced in the bone marrow and considered to be one of the major substances mediating hematotoxicity (Zhang et al, 2019).…”

From blood development to disease: a paradigm for clinical translation

“…Improved genome annotation, ease of husbandry and the development of genome editing (see, for example, Prykhozhij and Berman, 2018), xenotransplantation (Parada-Kusz et al, 2018) and imaging tools have helped propel the zebrafish to the forefront of hematopoiesis modeling (reviewed in Konantz et al, 2019). Indeed, zebrafish models have informed the basis for malignant transformation in the hematopoietic niche (Zhang et al, 2019;Gjini et al, 2019). In parallel, isogenic cell line pairs that allow researchers to model hematopoiesis and interrogate the precise functional consequences of disease-causing mutations can now be produced using genome editing in patient-derived iPSCs (reviewed in Georgomanoli and Papapetrou, 2019).…”