Environmental exposure to benzene occurs through cigarette smoke, unleaded gasoline and certain types of plastic. Benzene is converted to hematotoxic metabolites by the hepatic phase-I enzyme CYP2E1, and these metabolites are detoxified by the phase-II enzyme NQO1. The genes encoding these enzymes are highly polymorphic and studies of these polymorphisms have shown different pathogenic and prognostic features in various hematological malignancies. The potential role of different cytochrome p450 metabolizing enzymes in the pathogenesis of acute myeloid leukemia (AML) in an area of active interest. In this study, we demonstrate aberrant CYP2E1 mRNA over-expression by quantitative real-time polymerase chain reaction in 11 cases of de novo AML with inv(16); CBFβ-MYH11. CYP2E1 mRNA levels correlated with CBFβ-MYH11 transcript levels and with bone marrow blast counts in all cases. CYP2E1 over-expression correlated positively with NQO1 mRNA levels (R² = 0.934, n = 7). By immunohistochemistry, CYP2E1 protein was more frequently expressed in AML with inv(16) compared with other types of AML (p < 0.001). We obtained serial bone marrow samples from two patients with AML with inv(16) before and after treatment. CYP2E1 mRNA expression levels decreased in parallel with CBFβ-MYH11 transcript levels and blast counts following chemotherapy. In contrast, CYP1A2 transcript levels did not change in either patient. This is the first study to demonstrate concurrent over-expression of CYP2E1 and NQO1 mRNA in AML with inv(16). These findings also suggest that a balance between CYP2E1 and NQO1 may be important in the pathogenesis of AML with inv(16). Full article

We have applied bioinformatic approaches to identify pathways common to chemical leukemogens and to determine whether leukemogens could be distinguished from non-leukemogenic carcinogens. From all known and probable carcinogens classified by IARC and NTP, we identified 35 carcinogens that were associated with leukemia risk in human studies and 16 non-leukemogenic carcinogens. Using data on gene/protein targets available in the Comparative Toxicogenomics Database (CTD) for 29 of the leukemogens and 11 of the non-leukemogenic carcinogens, we analyzed for enrichment of all 250 human biochemical pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The top pathways targeted by the leukemogens included metabolism of xenobiotics by cytochrome P450, glutathione metabolism, neurotrophin signaling pathway, apoptosis, MAPK signaling, Toll-like receptor signaling and various cancer pathways. The 29 leukemogens formed 18 distinct clusters comprising 1 to 3 chemicals that did not correlate with known mechanism of action or with structural similarity as determined by 2D Tanimoto coefficients in the PubChem database. Unsupervised clustering and one-class support vector machines, based on the pathway data, were unable to distinguish the 29 leukemogens from 11 non-leukemogenic known and probable IARC carcinogens. However, using two-class random forests to estimate leukemogen and non-leukemogen patterns, we estimated a 76% chance of distinguishing a random leukemogen/non-leukemogen pair from each other. Full article

Recent research has spotlighted the role of microRNAs (miRNAs) as critical epigenetic regulators of hematopoietic stem cell differentiation and leukemia development. Despite the recent advances in knowledge surrounding epigenetics and leukemia, the mechanisms underlying miRNAs’ influence on leukemia development have yet to be clearly elucidated. Our aim was to identify high ranking biological pathways altered at the gene expression level and under epigenetic control. Specifically, we set out to test the hypothesis that miRNAs dysregulated in acute myeloid leukemia (AML) converge on a common pathway that can influence signaling related to hematopoiesis and leukemia development. We identified genes altered in AML patients that are under common regulation of seven key miRNAs. By mapping these genes to a global interaction network, we identified the “AML Signalisome”. The AML Signalisome comprises 53 AML-associated molecules, and is enriched for proteins that play a role in the aryl hydrocarbon receptor (AhR) pathway, a major regulator of hematopoiesis. Furthermore, we show biological enrichment for hematopoiesis-related proteins within the AML Signalisome. These findings provide important insight into miRNA-regulated pathways in leukemia, and may help to prioritize targets for disease prevention and treatment. Full article

Excessive exposure to benzene has been known for more than a century to damage the bone marrow resulting in decreases in the numbers of circulating blood cells, and ultimately, aplastic anemia. Of more recent vintage has been the appreciation that an alternative outcome of benzene exposure has been the development of one or more types of leukemia. While many investigators agree that the array of toxic metabolites, generated in the liver or in the bone marrow, can lead to traumatic bone marrow injury, the more subtle mechanisms leading to leukemia have yet to be critically dissected. This problem appears to have more general interest because of the recognition that so-called “second cancer” that results from prior treatment with alkylating agents to yield tumor remissions, often results in a type of leukemia reminiscent of benzene-induced leukemia. Furthermore, there is a growing literature attempting to characterize the fine structure of the marrow and the identification of so called “niches” that house a variety of stem cells and other types of cells. Some of these “niches” may harbor cells capable of initiating leukemias. The control of stem cell differentiation and proliferation via both inter- and intra-cellular signaling will ultimately determine the fate of these transformed stem cells. The ability of these cells to avoid checkpoints that would prevent them from contributing to the leukemogenic response is an additional area for study. Much of the study of benzene-induced bone marrow damage has concentrated on determining which of the benzene metabolites lead to leukemogenesis. The emphasis now should be directed to understanding how benzene metabolites alter bone marrow cell biology. Full article

Most antitumour therapies damage tumour cell DNA either directly or indirectly. Without repair, damage can result in genetic instability and eventually cancer. The strong association between the lack of DNA damage repair, mutations and cancer is dramatically demonstrated by a number of cancer-prone human syndromes, such as xeroderma pigmentosum, ataxia-telangiectasia and Fanconi anemia. Notably, DNA damage responses, and particularly DNA repair, influence the outcome of therapy. Because DNA repair normally excises lethal DNA lesions, it is intuitive that efficient repair will contribute to intrinsic drug resistance. Unexpectedly, a paradoxical relationship between DNA mismatch repair and drug sensitivity has been revealed by model studies in cell lines. This suggests that connections between DNA repair mechanism efficiency and tumour therapy might be more complex. Here, we review the evidence for the contribution of carcinogenic properties of several drugs as well as of alterations in specific mechanisms involved in drug-induced DNA damage response and repair in the pathogenesis of therapy-related cancers. Full article

Etoposide is an anticancer agent, which is successfully and extensively used in treatments for various types of cancers in children and adults. However, due to the increases in survival and overall cure rate of cancer patients, interest has arisen on the potential risk of this agent for therapy-related secondary leukemia. Topoisomerase II inhibitors, including etoposide and teniposide, frequently cause rearrangements involving the mixed lineage leukemia (MLL) gene on chromosome 11q23, which is associated with secondary leukemia. The prognosis is extremely poor for leukemias associated with rearrangements in the MLL gene, including etoposide-related secondary leukemias. It is of great importance to gain precise knowledge of the clinical aspects of these diseases and the mechanism underlying the leukemogenesis induced by this agent to ensure correct assessments of current and future therapy strategies. Here, I will review current knowledge regarding the clinical aspects of etoposide-related secondary leukemia, some probable mechanisms, and strategies for treating etoposide-induced leukemia. Full article

Type II DNA topoisomerases have the ability to generate a transient DNA double-strand break through which a second duplex can be passed; an activity essential for DNA decatenation and unknotting. Topoisomerase poisons stabilize the normally transient topoisomerase-induced DSBs and are potent and widely used anticancer drugs. However, their use is associated with therapy-related secondary leukemia, often bearing 11q23 translocations involving the MLL gene. We will explain recent discoveries in the fields of topoisomerase biology and transcription that have consequences for our understanding of the etiology of leukemia, especially therapy-related secondary leukemia and describe how these findings may help minimize the occurrence of these neoplasias. Full article