Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

Abstract

Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The distribution of breakpoints by exposure to non-cytotoxic levels of chemicals showed a similar pattern to fusion breakpoints in leukemia patients. Our findings demonstrate that HSPCs exposed to non-cytotoxic levels of environmental chemicals and chemotherapeutic agents are prone to topoisomerase II-mediated DNA damage at the leukemia-associated genes MLL and CBFB. These data suggest a role for long-term environmental chemical or residual chemotherapeutic drug exposure in generation of DNA breakage at sites with a propensity to form leukemia-causing gene rearrangements.

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“…MLL and FHIT genes (Thys et al, 2015). More evidence is needed to support the association of the aforementioned reported key events and the development of CL.…”

“…not immortalised) cells Bodell et al, 1996;Chung et al, 2002;Irons et al, 1992;Levay et al, 1993;Thys et al, 2015;Zhang et al, 1998).…”

“…On the other hand, primary human lymphocytes and bone marrow cells (including bone marrow haematopoietic stem cells) isolated from both humans and mice have been used to test the effects of benzene and its metabolites on healthy (i.e. not immortalised) cells Bodell et al, 1996;Chung et al, 2002;Irons et al, 1992;Levay et al, 1993;Robertson et al, 1991;Silva et al, 2004;Thys et al, 2015;Zhang et al, 1998).…”

“…Genotoxicity (e.g. DNA damage, formation of DNA adducts, chromosomal aberrations such as aneuploidy, increased formation of micronuclei and sister chromatid exchanges) of benzene and its metabolites (namely HQ, 1,4-BQ, 1,2,4-BT and catechol) is the most reported key event observed in the identified in vitro studies Bodell et al, 1996;Chung et al, 2002;Gaskell et al, 2005;Gurbani et al, 2012;Hedli et al, 1996;Ishihama et al, 2008;Levay & Bodell, 1992;Levay et al, 1993;Lindsey et al, 2005;Lindsey et al, 2004;Oikawa et al, 2001;Pandey et al, 2009;Pasquini et al, 2003;Robertson et al, 1991;Silva et al, 2004;Thys et al, 2015;Winn, 2003;Zhang et al, 1993;Zhang et al, 1994;Zhang et al, 1998). Then it is followed by oxidative stress as an early key event associated with benzene and its metabolites (Badham & Winn, 2010a;Goldman et al, 1999;Ishihama et al, 2008;Kolachana et al, 1993;Li & Trush, 1993;Nishikawa et al, 2012;Oikawa et al, 2001;Ruiz-Ramos et al, 2005;Shen et al, 1996;Wan & Winn, 2007;Wiemels & Smith, 1999;Zhang et al, 1993).…”

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“…Because CD34 + HSPCs appear to be more sensitive to DNA damage than committed progenitor cells, exposure to low levels of different chemicals may induce DNA breakage at certain sites in HSPCs, increasing the risk of chromosomal rearrangements Montecucco et al, 2015;Thys et al, 2015;Hern andez and Men endez, 2016). Studies on identical twins and neonatal blood samples strongly implicate an in utero occurrence of the key events .…”