PU.1 phosphorylation correlates with hydroquinone-induced alterations in myeloid differentiation and cytokine-dependent clonogenic response in human CD34+ hematopoietic progenitor cells

Zheng, Jia Hua; Le, Anh‐Tuan; Kerzic, Patrick; Irons, Richard D.

doi:10.1007/s10565-006-0128-7

Cited by 15 publications

(8 citation statements)

References 51 publications

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“…Both animal models and in vitro human cell cultures demonstrated that hydroquinone and para-benzoquinone are the active metabolites of benzene [ 15 , 16 ]. Additionally, it was shown that hydroquinone induces cell changes that are consistent with various cellular changes known to mark the early progression of AML in humans [ 16 , 17 ]. These molecular-level studies supported available human in vivo data (i.e., standard epidemiological studies), thereby lessening the need for additional observational studies to support a causal relationship.…”

Section: Criteria 2: Consistencymentioning

confidence: 95%

Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology

Fedak

Bernal²,

Capshaw

et al. 2015

Emerg Themes Epidemiol

508

370

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In 1965, Sir Austin Bradford Hill published nine “viewpoints” to help determine if observed epidemiologic associations are causal. Since then, the “Bradford Hill Criteria” have become the most frequently cited framework for causal inference in epidemiologic studies. However, when Hill published his causal guidelines—just 12 years after the double-helix model for DNA was first suggested and 25 years before the Human Genome Project began—disease causation was understood on a more elementary level than it is today. Advancements in genetics, molecular biology, toxicology, exposure science, and statistics have increased our analytical capabilities for exploring potential cause-and-effect relationships, and have resulted in a greater understanding of the complexity behind human disease onset and progression. These additional tools for causal inference necessitate a re-evaluation of how each Bradford Hill criterion should be interpreted when considering a variety of data types beyond classic epidemiology studies. Herein, we explore the implications of data integration on the interpretation and application of the criteria. Using examples of recently discovered exposure–response associations in human disease, we discuss novel ways by which researchers can apply and interpret the Bradford Hill criteria when considering data gathered using modern molecular techniques, such as epigenetics, biomarkers, mechanistic toxicology, and genotoxicology.

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Section: Criteria 2: Consistencymentioning

confidence: 95%

Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology

Fedak

Bernal²,

Capshaw

et al. 2015

Emerg Themes Epidemiol

508

370

View full text Add to dashboard Cite

show abstract

“…HQ-induced dysregulation of external signals modulating the protein phosphorylation of the transcriptional regulator, PU.1, may promote the clonal proliferation of CD34þ cells (187). HQ was shown to alter the pattern of binding of PU.1 to DNA in a time-and Mechanism of benzene-induced leukemia dose-dependent manner and to induce hyperphosphorylation of the PU.1 protein, in cultured human CD34þ cells.…”

Section: Dysregulation Of the Hsc Niche Leads To Increased Proliferationmentioning

confidence: 97%

Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment

McHale¹,

Zhang²,

Smith³

2011

Carcinogenesis

272

196

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Benzene causes acute myeloid leukemia and probably other hematological malignancies. As benzene also causes hematotoxicity even in workers exposed to levels below the US permissible occupational exposure limit of 1 part per million, further assessment of the health risks associated with its exposure, particularly at low levels, is needed. Here, we describe the probable mechanism by which benzene induces leukemia involving the targeting of critical genes and pathways through the induction of genetic, chromosomal or epigenetic abnormalities and genomic instability, in a hematopoietic stem cell (HSC); stromal cell dysregulation; apoptosis of HSCs and stromal cells and altered proliferation and differentiation of HSCs. These effects modulated by benzene-induced oxidative stress, aryl hydrocarbon receptor dysregulation and reduced immunosurveillance, lead to the generation of leukemic stem cells and subsequent clonal evolution to leukemia. A mode of action (MOA) approach to the risk assessment of benzene was recently proposed. This approach is limited, however, by the challenges of defining a simple stochastic MOA of benzene-induced leukemogenesis and of identifying relevant and quantifiable parameters associated with potential key events. An alternative risk assessment approach is the application of toxicogenomics and systems biology in human populations, animals and in vitro models of the HSC stem cell niche, exposed to a range of levels of benzene. These approaches will inform our understanding of the mechanisms of benzene toxicity and identify additional biomarkers of exposure, early effect and susceptibility useful for risk assessment.

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“…t (15,17), t (8,21), Flt3 mutations) were associated with decreased PU.1 expression in AML M3 and in some cases of AML M2; [20][21][22][23] (c) PU.1 protein hyperphosphorylation was observed in some subtypes of AML. 24 Iron et al 25 exposed human CD34 þ to hydroxyquinone, a benzene metabolite, and found a marked PU.1 hyperphosphorylation, associated with an enhanced clonogenic activity and a block in myeloid differentiation. These studies could eventually explain the link between chronic exposure to high concentrations of benzene and AML development; (d) recently, two transcription factors of the Jun family were identified as PU.1 target genes.…”

Section: Introductionmentioning

confidence: 99%

Lentiviral PU.1 overexpression restores differentiation in myeloid leukemic blasts

et al. 2007

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PU.1 phosphorylation correlates with hydroquinone-induced alterations in myeloid differentiation and cytokine-dependent clonogenic response in human CD34+ hematopoietic progenitor cells

Cited by 15 publications

References 51 publications

Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology

Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology

Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment

Lentiviral PU.1 overexpression restores differentiation in myeloid leukemic blasts

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