Special Issue "Leukemia Arising from Chemical Exposures and Chemotherapeutic Drugs"

Guest Editor
Dr. Luoping Zhang
Division of Environmental Health Sciences, School of Public Health, University of California at Berkeley, Berkeley, CA 94720, USA
Website: http://sph.berkeley.edu/faculty/zhang.php
E-Mail: luoping@berkeley.edu
Phone: +1 510 643 5189
Fax: +1 510 642 0427
Interests: the impact and mechanisms of exposures to toxic chemicals on human health, particularly in carcinogenesis and leukemogenesis; application of omic technologies in molecular epidemiological studies; and the development of new tools and assays to explore relevant biomakers

Dear Colleagues,

The etiology of the blood cancer leukemia is still largely unknown; however, exposures to toxic chemicals and cancer-therapeutic drugs can cause leukemia in adults and children. Benzene is a well established leukemogen and occupational exposure to formaldehyde has recently been shown to increase leukemia risk. Additionally, a portion of primary cancer patients develop acute myeloid leukemia (AML) after treatment with chemotherapeutic drugs, such as alkylating agents (melphalan etc) and DNA topoisomerase II (Topo II) inhibitors (etoposide etc.). Evidence suggests that the leukemia associated with exposure to different types of leukemogen exhibits specific molecular changes. For instance, therapy-related AML resulting from treatment with alkylating agents is mainly associated with loss of chromosomes 5 and 7, while Topo II inhibitor-induced AML is commonly associated with chromosomal translocations. Although chromosomal aneuploidy and rearrangements are hallmarks of leukemia, it is not well understood how these chemicals interact with normal hematopoietic stem/progenitor cells and disrupt bone marrow niches. This special issue will focus on molecular (genetic and epigenetic) mechanisms of chemically-induced leukmogenesis in exposed humans, experimental animal models and in vitro systems. We will accept original research reports, short communications/commentaries, and limited review papers deemed relevant.

Dr. Luoping Zhang
Guest Editor

Submission

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• Leukemogenesis
• Leukemogen
• Benzene
• Formaldehyde
• Therapy-related leukemia
• Alkylating agents
• DNA topoisomerase II inhibitors
• Mechanisms

Type of Paper: Article
Title: The Aryl Hydrocarbon Receptor Pathway: A Key Component of the miRNA-Mediated AML Signalisome
Auhtors: Julia E. Rager¹ and Rebecca C. Fry^{1,2
Affiliation: 1} Department of Environmental Sciences and Engineering, Gillings School of Global Public Health
² Curriculum in Toxicology, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, USA
Abstract: 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 insight into the pathophysiological mechanisms underlying leukemogenesis, and may help to prioritize targeted pathways for disease prevention and treatment.
Keywords: aryl hydrocarbon receptor; gene expression; leukemia; microRNA; systems biology

Title: Mechanism of Generation of Therapy Related Leukemia, in Response to Anti-Topoisomerase II Agents
Authors: Ian G. Cowell and Caroline A. Austin
Affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; E-Mail: ian.cowell@ncl.ac.uk
Abstract: 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 stabilise the normally transient topo-induced DSBs and are potent and widely used anticancer drugs. However, their use is associated with therapy-related secondary leukaemia, 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 aetiology of leukemia, especially therapy-related secondary leukemia and describe how these findings may help minimize the occurrence of these neoplasias.

Title: Chemicals Causing Leukemias/lymphomas in Laboratory Animals and in Humans
Author: James Huff
Affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 USA; E-Mail: huff1@niehs.nih.gov
Abstract: First chemical identified causing leukemia in humans occurred in the early 20th century. Before that the widely used industrial solvent benzene was even considered and prescribed medically for various blood disorders. Other than cancer chemotherapeutic agents, few other chemicals have been causally associated with leukemia/lymphoma in humans. A recent example is formaldehyde, declared leukemogenic to humans by IARC and NTP in 2009. Another is 1,3-butadiene used in the rubber industry. Both were first shown to be carcinogenic in animals. Of the ~600 chemicals studied for carcinogenic activity by National Cancer Institute and National Toxicology Program, 39 chemicals [~7%] caused tumors of the hematopoietic system: male rats, 15; female rats, 15; male mice, 11, female mice, 16. Only one chemical [procarbazine hydrochloride] caused leukemia/lymphoma in each of four sex-species experiments; one in 3 of 4 [tris(aziridinyl)-phosphine sulfide (thio-tepa)]; 13 in 2 of 4; and 24 in 1 of 4. Six chemicals caused only tumors of the hematopoietic system. Experimental results from these long-term carcinogenesis bioassays are detailed.

Title: Identification of mechanisms common to chemical leukemogens by bioinformatic analysis
Authors: Jimmy Phuong, Reuben Thomas, Cliona M. McHale, Luoping Zhang
Affiliation: Genes and Environment Laboratory, School of Public Health, University of California, Berkeley, CA 94720, USA
Abstract: Though environmental factors are thought to account for ~80 % of the risk of leukemia, few leukemogens have been conclusively identified. We sought to identify common pathways targeted by known chemical leukemogens that could be used to identify additional potential leukemogens. Data on gene/protein targets was available in the Comparative Toxicogenomics Database for 32 of the 122 chemicals classified as known or probable leukemogens by the International Association for Cancer Research or the National Toxicology Program. We analyzed the set of gene/protein targets targeted by each chemical for enrichment in all 250 human biochemical pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and performed unsupervised clustering of the resulting pathways. Six groups of KEGG pathways were identified among those (n=110) with targets for most leukemogens. Two groups were associated with cell cycle and cancer/disease-related pathways; three with Toll-like receptor, B-cell signaling and other immune and infectious diseases pathways; and, one with the fatty acid metabolism and metabolism of xenobiotics with cytochrome P450. The 32 leukemogens formed three distinct clusters, suggesting common mechanisms of action. Three well-known leukemogens, benzene, etoposide, and 1,3-butadiene, were in separate clusters. These mechanistic signatures could aid in the identification of potential leukemogens.
Keywords: Leukemia; carcinogens; bioinformatics; enriched pathways