Bariar Bhawana, Vestal C Greer, Deem Bradley, Goodenow Donna, Ughetta Mimi, Engledove R Warren, Sahyouni Mark, Richardson Christine
Department of Biological Sciences, University of North Carolina at Charlotte, 9201 University City Boulevard, Charlotte, North Carolina.
Environ Mol Mutagen. 2019 Mar;60(2):154-167. doi: 10.1002/em.22245. Epub 2018 Nov 2.
Infant acute leukemias are aggressive and characterized by rapid onset after birth. The majority harbor translocations involving the MLL gene with AF9 as one of its most common fusion partners. MLL and AF9 loci contain breakpoint cluster regions (bcrs) with sequences hypothesized to be targets of topoisomerase II inhibitors that promote translocation formation. Overlap of MLL bcr sequences associated with both infant acute leukemia and therapy-related leukemia following exposure to the topoisomerase II inhibitor etoposide led to the hypothesis that exposure during pregnancy to biochemically similar compounds may promote infant acute leukemia. We established a reporter system to systematically quantitate and stratify the potential for such compounds to promote chromosomal translocations between the MLL and AF9 bcrs analogous to those in infant leukemia. We show bioflavonoids genistein and quercetin most biochemically similar to etoposide have a strong association with MLL-AF9 bcr translocations, while kaempferol, fisetin, flavone, and myricetin have a weak but consistent association, and other compounds have a minimal association in both embryonic stem (ES) and hematopoietic stem cell (HSC) populations. The frequency of translocations induced by bioflavonoids at later stages of myelopoiesis is significantly reduced by more than one log. The MLL and AF9 bcrs are sensitive to these agents and recombinogenic independent of their native context suggesting bcr sequences themselves are drivers of illegitimate DNA repair reactions and translocations, not generation of functional oncogenic fusions. This system provides for rapid systematic screening of relative risk, dose dependence, and combinatorial impact of multitudes of dietary and environmental exposures on MLL-AF9 translocations. Environ. Mol. Mutagen. 60: 154-167, 2019. © 2018 Wiley Periodicals, Inc.
婴儿急性白血病具有侵袭性，其特征是出生后起病迅速。大多数病例存在涉及MLL基因的易位，AF9是其最常见的融合伴侣之一。MLL和AF9基因座包含断点簇区域（bcr），其序列被推测为拓扑异构酶II抑制剂的作用靶点，这些抑制剂可促进易位形成。与婴儿急性白血病以及接触拓扑异构酶II抑制剂依托泊苷后发生的治疗相关白血病相关的MLL bcr序列存在重叠，这引发了一种假说，即孕期接触生化性质相似的化合物可能会促进婴儿急性白血病的发生。我们建立了一个报告系统，以系统地定量和分层此类化合物促进MLL和AF9 bcr之间染色体易位的可能性，这种易位类似于婴儿白血病中的易位。我们发现，与依托泊苷生化性质最相似的生物类黄酮染料木黄酮和槲皮素与MLL-AF9 bcr易位有很强的关联，而山奈酚、漆黄素、黄酮和杨梅素的关联较弱但一致，其他化合物在胚胎干细胞（ES）和造血干细胞（HSC）群体中的关联最小。生物类黄酮在髓系造血后期诱导的易位频率显著降低超过一个对数。MLL和AF9 bcr对这些试剂敏感且具有重组活性，与它们的天然背景无关，这表明bcr序列本身是非法DNA修复反应和易位的驱动因素，而非功能性致癌融合的产生因素。该系统可快速系统地筛选多种饮食和环境暴露对MLL-AF9易位的相对风险、剂量依赖性和组合影响。《环境与分子突变》。2019年第60卷：154 - 167页。© 2018威利期刊公司。
