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• W2956003848 abstract "Protein tyrosine phosphatase, nonreceptor type 2 (PTPN2) is mainly expressed in hematopoietic cells, where it negatively regulates growth factor and cytokine signaling. PTPN2 is an important regulator of hematopoiesis and immune/inflammatory responses, as evidenced by loss-of-function mutations of PTPN2 in leukemia and lymphoma and knockout mice studies. Benzene is an environmental chemical that causes hematological malignancies, and its hematotoxicity arises from its bioactivation in the bone marrow to electrophilic metabolites, notably 1,4-benzoquinone, a major hematotoxic benzene metabolite. Although the molecular bases for benzene-induced leukemia are not well-understood, it has been suggested that benzene metabolites alter topoisomerases II function and thereby significantly contribute to leukemogenesis. However, several studies indicate that benzene and its hematotoxic metabolites may also promote the leukemogenic process by reacting with other targets and pathways. Interestingly, alterations of cell-signaling pathways, such as Janus kinase (JAK)/signal transducer and activator of transcription (STAT), have been proposed to contribute to benzene-induced malignant blood diseases. We show here that 1,4-benzoquinone directly impairs PTPN2 activity. Mechanistic and kinetic experiments with purified human PTPN2 indicated that this impairment results from the irreversible formation (kinact = 645 m−1·s−1) of a covalent 1,4-benzoquinone adduct at the catalytic cysteine residue of the enzyme. Accordingly, cell experiments revealed that 1,4-benzoquinone exposure irreversibly inhibits cellular PTPN2 and concomitantly increases tyrosine phosphorylation of STAT1 and expression of STAT1-regulated genes. Our results provide molecular and cellular evidence that 1,4-benzoquinone covalently modifies key signaling enzymes, implicating it in benzene-induced malignant blood diseases. Protein tyrosine phosphatase, nonreceptor type 2 (PTPN2) is mainly expressed in hematopoietic cells, where it negatively regulates growth factor and cytokine signaling. PTPN2 is an important regulator of hematopoiesis and immune/inflammatory responses, as evidenced by loss-of-function mutations of PTPN2 in leukemia and lymphoma and knockout mice studies. Benzene is an environmental chemical that causes hematological malignancies, and its hematotoxicity arises from its bioactivation in the bone marrow to electrophilic metabolites, notably 1,4-benzoquinone, a major hematotoxic benzene metabolite. Although the molecular bases for benzene-induced leukemia are not well-understood, it has been suggested that benzene metabolites alter topoisomerases II function and thereby significantly contribute to leukemogenesis. However, several studies indicate that benzene and its hematotoxic metabolites may also promote the leukemogenic process by reacting with other targets and pathways. Interestingly, alterations of cell-signaling pathways, such as Janus kinase (JAK)/signal transducer and activator of transcription (STAT), have been proposed to contribute to benzene-induced malignant blood diseases. We show here that 1,4-benzoquinone directly impairs PTPN2 activity. Mechanistic and kinetic experiments with purified human PTPN2 indicated that this impairment results from the irreversible formation (kinact = 645 m−1·s−1) of a covalent 1,4-benzoquinone adduct at the catalytic cysteine residue of the enzyme. Accordingly, cell experiments revealed that 1,4-benzoquinone exposure irreversibly inhibits cellular PTPN2 and concomitantly increases tyrosine phosphorylation of STAT1 and expression of STAT1-regulated genes. Our results provide molecular and cellular evidence that 1,4-benzoquinone covalently modifies key signaling enzymes, implicating it in benzene-induced malignant blood diseases. Benzene is an organic compound of great industrial importance used as a solvent or starting material for the synthesis of numerous chemicals. It is also found in gasoline vapors, motor vehicle exhaust, burning coal and oil, cigarette smoke, and wood-burning fires (1Smith M.T. Zhang L. McHale C.M. Skibola C.F. Rappaport S.M. Benzene, the exposome and future investigations of leukemia etiology.Chem. Biol. Interact. 2011; 192 (21333640): 155-15910.1016/j.cbi.2011.02.010Crossref PubMed Scopus (91) Google Scholar, 2Snyder R. Leukemia and benzene.Int. J. Environ. Res. Public Health. 2012; 9 (23066403): 2875-289310.3390/ijerph9082875Crossref PubMed Scopus (144) Google Scholar). Benzene has long been recognized as a group 1 carcinogen, and exposure to benzene is now established as a cause of hematological malignancies in humans (1Smith M.T. Zhang L. McHale C.M. Skibola C.F. Rappaport S.M. Benzene, the exposome and future investigations of leukemia etiology.Chem. Biol. Interact. 2011; 192 (21333640): 155-15910.1016/j.cbi.2011.02.010Crossref PubMed Scopus (91) Google Scholar, 3Wang L. He X. Bi Y. Ma Q. Stem cell and benzene-induced malignancy and hematotoxicity.Chem. Res. Toxicol. 2012; 25 (22540379): 1303-131510.1021/tx3001169Crossref PubMed Scopus (48) Google Scholar4McHale C.M. Zhang L. Lan Q. Vermeulen R. Li G. Hubbard A.E. Porter K.E. Thomas R. Portier C.J. Shen M. Rappaport S.M. Yin S. Smith M.T. Rothman N. Global gene expression profiling of a population exposed to a range of benzene levels.Environ. Health Perspect. 2011; 119 (21147609): 628-63410.1289/ehp.1002546Crossref PubMed Scopus (86) Google Scholar, 5Greim H. Kaden D.A. Larson R.A. Palermo C.M. Rice J.M. Ross D. Snyder R. The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment.Ann. N.Y. Acad. Sci. 2014; 1310 (24495159): 7-3110.1111/nyas.12362Crossref PubMed Scopus (29) Google Scholar, 6Loomis D. Guyton K.Z. Grosse Y. El Ghissassi F. Bouvard V. Benbrahim-Tallaa L. Guha N. Vilahur N. Mattock H. Straif K. International Agency for Research on Cancer Monograph Working Group Carcinogenicity of benzene.Lancet Oncol. 2017; 18 (29107678): 1574-157510.1016/S1470-2045(17)30832-XAbstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar7Goldstein B.D. Hematological and toxicological evaluation of formaldehyde as a potential cause of human leukemia.Hum. Exp. Toxicol. 2011; 30 (20729258): 725-73510.1177/0960327110381682Crossref PubMed Scopus (29) Google Scholar). Recent studies indicate that benzene is one of the major carcinogen air toxics that affect public health significantly in the United States (8Zhou Y. Li C. Huijbregts M.A. Mumtaz M.M. Carcinogenic air toxics exposure and their cancer-related health impacts in the United States.PLoS One. 2015; 10 (26444872): e014001310.1371/journal.pone.0140013PubMed Google Scholar). To become carcinogenic and cause leukemia, benzene must be metabolized in the bone marrow to electrophilic metabolites, such as 1,4-benzoquinone, which are considered as the ultimate hematotoxic species (1Smith M.T. Zhang L. McHale C.M. Skibola C.F. Rappaport S.M. Benzene, the exposome and future investigations of leukemia etiology.Chem. Biol. Interact. 2011; 192 (21333640): 155-15910.1016/j.cbi.2011.02.010Crossref PubMed Scopus (91) Google Scholar, 4McHale C.M. Zhang L. Lan Q. Vermeulen R. Li G. Hubbard A.E. Porter K.E. Thomas R. Portier C.J. Shen M. Rappaport S.M. Yin S. Smith M.T. Rothman N. Global gene expression profiling of a population exposed to a range of benzene levels.Environ. Health Perspect. 2011; 119 (21147609): 628-63410.1289/ehp.1002546Crossref PubMed Scopus (86) Google Scholar, 9Frantz C.E. Chen H. Eastmond D.A. Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites.Environ. Health Perspect. 1996; 104 (9118913): 1319-132310.1289/ehp.961041319Crossref PubMed Scopus (59) Google Scholar, 10Whysner J. Reddy M.V. Ross P.M. Mohan M. Lax E.A. Genotoxicity of benzene and its metabolites.Mutat. Res. 2004; 566 (15164977): 99-13010.1016/S1383-5742(03)00053-XCrossref PubMed Scopus (142) Google Scholar11Kolachana P. Subrahmanyam V.V. Meyer K.B. Zhang L. Smith M.T. Benzene and its phenolic metabolites produce oxidative DNA damage in HL60 cells in vitro and in the bone marrow in vivo.Cancer Res. 1993; 53 (8439949): 1023-1026PubMed Google Scholar), yet the molecular mechanisms by which benzene and its metabolites exert their leukemogenic effects have not been fully elucidated (1Smith M.T. Zhang L. McHale C.M. Skibola C.F. Rappaport S.M. Benzene, the exposome and future investigations of leukemia etiology.Chem. Biol. Interact. 2011; 192 (21333640): 155-15910.1016/j.cbi.2011.02.010Crossref PubMed Scopus (91) Google Scholar, 12Meek B. Cloosen S. Borsotti C. Van Elssen C.H. Vanderlocht J. Schnijderberg M.C. van der Poel M.W. Leewis B. Hesselink R. Manz M.G. Katsura Y. Kawamoto H. Germeraad W.T. Bos G.M. In vitro-differentiated T/natural killer-cell progenitors derived from human CD34+ cells mature in the thymus.Blood. 2010; 115 (19828700): 261-26410.1182/blood-2009-05-223990Crossref PubMed Scopus (27) Google Scholar13Zhang L. McHale C.M. Rothman N. Li G. Ji Z. Vermeulen R. Hubbard A.E. Ren X. Shen M. Rappaport S.M. North M. Skibola C.F. Yin S. Vulpe C. Chanock S.J. Smith M.T. Lan Q. Systems biology of human benzene exposure.Chem. Biol. Interact. 2010; 184 (20026094): 86-9310.1016/j.cbi.2009.12.011Crossref PubMed Scopus (79) Google Scholar, 14Eastmond D.A. Keshava N. Sonawane B. Lymphohematopoietic cancers induced by chemicals and other agents and their implications for risk evaluation: an overview.Mutat. Res. Rev. Mutat. Res. 2014; 761 (24731989): 40-6410.1016/j.mrrev.2014.04.001Crossref Scopus (28) Google Scholar15Sauer E. Gauer B. Nascimento S. Nardi J. Göethel G. Costa B. Correia D. Matte U. Charão M. Arbo M. Duschl A. Moro A. Garcia S.C. The role of B7 costimulation in benzene immunotoxicity and its potential association with cancer risk.Environ. Res. 2018; 166 (29883905): 91-9910.1016/j.envres.2018.05.029Crossref PubMed Scopus (13) Google Scholar). Although oxidative DNA damage and chromosome alteration through alteration of topoisomerases II functions by benzene metabolites have been shown as contributors to benzene-induced leukemia, mounting evidence indicates that additional mechanisms are also involved (1Smith M.T. Zhang L. McHale C.M. Skibola C.F. Rappaport S.M. Benzene, the exposome and future investigations of leukemia etiology.Chem. Biol. Interact. 2011; 192 (21333640): 155-15910.1016/j.cbi.2011.02.010Crossref PubMed Scopus (91) Google Scholar, 2Snyder R. Leukemia and benzene.Int. J. Environ. Res. Public Health. 2012; 9 (23066403): 2875-289310.3390/ijerph9082875Crossref PubMed Scopus (144) Google Scholar, 4McHale C.M. Zhang L. Lan Q. Vermeulen R. Li G. Hubbard A.E. Porter K.E. Thomas R. Portier C.J. Shen M. Rappaport S.M. Yin S. Smith M.T. Rothman N. Global gene expression profiling of a population exposed to a range of benzene levels.Environ. Health Perspect. 2011; 119 (21147609): 628-63410.1289/ehp.1002546Crossref PubMed Scopus (86) Google Scholar, 12Meek B. Cloosen S. Borsotti C. Van Elssen C.H. Vanderlocht J. Schnijderberg M.C. van der Poel M.W. Leewis B. Hesselink R. Manz M.G. Katsura Y. Kawamoto H. Germeraad W.T. Bos G.M. In vitro-differentiated T/natural killer-cell progenitors derived from human CD34+ cells mature in the thymus.Blood. 2010; 115 (19828700): 261-26410.1182/blood-2009-05-223990Crossref PubMed Scopus (27) Google Scholar, 15Sauer E. Gauer B. Nascimento S. Nardi J. Göethel G. Costa B. Correia D. Matte U. Charão M. Arbo M. Duschl A. Moro A. Garcia S.C. The role of B7 costimulation in benzene immunotoxicity and its potential association with cancer risk.Environ. Res. 2018; 166 (29883905): 91-9910.1016/j.envres.2018.05.029Crossref PubMed Scopus (13) Google Scholar, 16Gross S.A. Paustenbach D.J. Shanghai Health Study (2001–2009): What was learned about benzene health effects?.Crit. Rev. Toxicol. 2018; 48 (29243948): 217-25110.1080/10408444.2017.1401581Crossref PubMed Scopus (21) Google Scholar). Alteration of critical hematopoietic cell signaling pathways has been recently proposed as a relevant mechanism by which benzene could induce hematotoxicity and leukemia (1Smith M.T. Zhang L. McHale C.M. Skibola C.F. Rappaport S.M. Benzene, the exposome and future investigations of leukemia etiology.Chem. Biol. Interact. 2011; 192 (21333640): 155-15910.1016/j.cbi.2011.02.010Crossref PubMed Scopus (91) Google Scholar, 2Snyder R. Leukemia and benzene.Int. J. Environ. Res. Public Health. 2012; 9 (23066403): 2875-289310.3390/ijerph9082875Crossref PubMed Scopus (144) Google Scholar, 4McHale C.M. Zhang L. Lan Q. Vermeulen R. Li G. Hubbard A.E. Porter K.E. Thomas R. Portier C.J. Shen M. Rappaport S.M. Yin S. Smith M.T. Rothman N. Global gene expression profiling of a population exposed to a range of benzene levels.Environ. Health Perspect. 2011; 119 (21147609): 628-63410.1289/ehp.1002546Crossref PubMed Scopus (86) Google Scholar, 17Minciullo P.L. Navarra M. Calapai G. Gangemi S. Cytokine network involvement in subjects exposed to benzene.J. Immunol. Res. 2014; 2014 (25202711): 93798710.1155/2014/937987Crossref PubMed Scopus (27) Google Scholar). In addition, recent data indicate that chronic inflammation and aberrant immune response are likely to play a role in benzene-induced malignancies (15Sauer E. Gauer B. Nascimento S. Nardi J. Göethel G. Costa B. Correia D. Matte U. Charão M. Arbo M. Duschl A. Moro A. Garcia S.C. The role of B7 costimulation in benzene immunotoxicity and its potential association with cancer risk.Environ. Res. 2018; 166 (29883905): 91-9910.1016/j.envres.2018.05.029Crossref PubMed Scopus (13) Google Scholar, 16Gross S.A. Paustenbach D.J. Shanghai Health Study (2001–2009): What was learned about benzene health effects?.Crit. Rev. Toxicol. 2018; 48 (29243948): 217-25110.1080/10408444.2017.1401581Crossref PubMed Scopus (21) Google Scholar). Interestingly, global gene expression profiling studies showed that key hematopoietic and immune signaling processes, notably the JAK 6The abbreviations used are: JAKJanus kinaseSTATsignal transducers and activators of transcriptionPTPprotein tyrosine phosphatasePTPN2protein tyrosine phosphatase, non-receptor type 2BQ1,4-benzoquinoneHQhydroquinoneMPOmyeloperoxidaseNBTnitro blue tetrazoliumIAFfluorescein-iodoacetamidePBGplumbaginpNPPpara-nitrophenyl phosphateNEMN-ethylmaleimideFAformic acidACNacetonitrileIFNinterferonqPCRquantitative PCR. /STAT pathway, were altered in individuals occupationally exposed to benzene (4McHale C.M. Zhang L. Lan Q. Vermeulen R. Li G. Hubbard A.E. Porter K.E. Thomas R. Portier C.J. Shen M. Rappaport S.M. Yin S. Smith M.T. Rothman N. Global gene expression profiling of a population exposed to a range of benzene levels.Environ. Health Perspect. 2011; 119 (21147609): 628-63410.1289/ehp.1002546Crossref PubMed Scopus (86) Google Scholar). Janus kinase signal transducers and activators of transcription protein tyrosine phosphatase protein tyrosine phosphatase, non-receptor type 2 1,4-benzoquinone hydroquinone myeloperoxidase nitro blue tetrazolium fluorescein-iodoacetamide plumbagin para-nitrophenyl phosphate N-ethylmaleimide formic acid acetonitrile interferon quantitative PCR. Maintenance of cellular homeostasis in the hematopoietic system requires the STAT transcription factors, which are activated through tyrosine phosphorylation by a variety of cytokines and growth factors (18Baker S.J. Rane S.G. Reddy E.P. Hematopoietic cytokine receptor signaling.Oncogene. 2007; 26 (17934481): 6724-673710.1038/sj.onc.1210757Crossref PubMed Scopus (208) Google Scholar, 19Dorritie K.A. Redner R.L. Johnson D.E. STAT transcription factors in normal and cancer stem cells.Adv. Biol. Regul. 2014; 56 (24931719): 30-4410.1016/j.jbior.2014.05.004Crossref PubMed Scopus (29) Google Scholar). However, aberrant activation of STAT proteins and subsequent dysregulation of STAT signaling are associated with leukemic transformation and altered immune response (19Dorritie K.A. Redner R.L. Johnson D.E. STAT transcription factors in normal and cancer stem cells.Adv. Biol. Regul. 2014; 56 (24931719): 30-4410.1016/j.jbior.2014.05.004Crossref PubMed Scopus (29) Google Scholar, 20Benekli M. Baumann H. Wetzler M. Targeting signal transducer and activator of transcription signaling pathway in leukemias.J. Clin. Oncol. 2009; 27 (19667270): 4422-443210.1200/JCO.2008.21.3264Crossref PubMed Scopus (115) Google Scholar21O'Shea K.M. Hwang S.A. Actor J.K. Immune activity of BCG infected mouse macrophages treated with a novel recombinant mouse lactoferrin.Ann. Clin. Lab. Sci. 2015; 45 (26586698): 487-494PubMed Google Scholar). Protein tyrosine phosphatases (PTPs) play a major role in the down-modulation of STAT signaling in the hematopoietic system through dephosphorylation of JAK and/or STAT proteins (18Baker S.J. Rane S.G. Reddy E.P. Hematopoietic cytokine receptor signaling.Oncogene. 2007; 26 (17934481): 6724-673710.1038/sj.onc.1210757Crossref PubMed Scopus (208) Google Scholar, 19Dorritie K.A. Redner R.L. Johnson D.E. STAT transcription factors in normal and cancer stem cells.Adv. Biol. Regul. 2014; 56 (24931719): 30-4410.1016/j.jbior.2014.05.004Crossref PubMed Scopus (29) Google Scholar, 22Tonks N.K. Protein tyrosine phosphatases: from genes, to function, to disease.Nat. Rev. Mol. Cell Biol. 2006; 7 (17057753): 833-84610.1038/nrm2039Crossref PubMed Scopus (1253) Google Scholar, 23Böhmer F.D. Friedrich K. Protein tyrosine phosphatases as wardens of STAT signaling.JAKSTAT. 2014; 3 (24778927): e2808710.4161/jkst.28087PubMed Google Scholar). PTPN2 (also known as TCPTP, for T cell protein tyrosine phosphatase) is an intracellular tyrosine phosphatase highly expressed in hematopoietic cells, where it serves as a key regulator of hematopoiesis and immune and inflammatory responses (24Tiganis T. Bennett A.M. Protein tyrosine phosphatase function: the substrate perspective.Biochem. J. 2007; 402 (17238862): 1-1510.1042/BJ20061548Crossref PubMed Scopus (223) Google Scholar, 25Pike K.A. Tremblay M.L. TC-PTP and PTP1B: regulating JAK-STAT signaling, controlling lymphoid malignancies.Cytokine. 2016; 82 (26817397): 52-5710.1016/j.cyto.2015.12.025Crossref PubMed Scopus (45) Google Scholar). PTPN2 deficiency in mice (PTPN2−/PTPN2−) induces severe hematopoietic defects (affecting lymphoid, myeloid, and erythroid lineages) and progressive systemic inflammation leading to death of the knockout mice within weeks (26You-Ten K.E. Muise E.S. Itié A. Michaliszyn E. Wagner J. Jothy S. Lapp W.S. Tremblay M.L. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice.J. Exp. Med. 1997; 186 (9271584): 683-69310.1084/jem.186.5.683Crossref PubMed Scopus (316) Google Scholar27Bourdeau A. Dubé N. Heinonen K.M. Théberge J.F. Doody K.M. Tremblay M.L. TC-PTP-deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ.Blood. 2007; 109 (17234741): 4220-422810.1182/blood-2006-08-044370Crossref PubMed Scopus (39) Google Scholar, 28Heinonen K.M. Bourdeau A. Doody K.M. Tremblay M.L. Protein tyrosine phosphatases PTP-1B and TC-PTP play nonredundant roles in macrophage development and IFN-γ signaling.Proc. Natl. Acad. Sci. U.S.A. 2009; 106 (19474293): 9368-937210.1073/pnas.0812109106Crossref PubMed Scopus (59) Google Scholar29Wiede F. Chew S.H. van Vliet C. Poulton I.J. Kyparissoudis K. Sasmono T. Loh K. Tremblay M.L. Godfrey D.I. Sims N.A. Tiganis T. Strain-dependent differences in bone development, myeloid hyperplasia, morbidity and mortality in ptpn2-deficient mice.PLoS One. 2012; 7 (22590589): e3670310.1371/journal.pone.0036703Crossref PubMed Scopus (28) Google Scholar). In humans, deletions or inactivating mutations of PTPN2 were identified in T-cell leukemia and non-Hodgkin’s lymphoma and associated with elevated STAT signaling and changes in gene expression (25Pike K.A. Tremblay M.L. TC-PTP and PTP1B: regulating JAK-STAT signaling, controlling lymphoid malignancies.Cytokine. 2016; 82 (26817397): 52-5710.1016/j.cyto.2015.12.025Crossref PubMed Scopus (45) Google Scholar, 30Kleppe M. Lahortiga I. El Chaar T. De Keersmaecker K. Mentens N. Graux C. Van Roosbroeck K. Ferrando A.A. Langerak A.W. Meijerink J.P. Sigaux F. Haferlach T. Wlodarska I. Vandenberghe P. Soulier J. Cools J. Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia.Nat. 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In addition, loss of PTPN2 may also contribute to resistance of chronic myeloid cells to imatinib through the modulation of PTPN2-dependent signals downstream of the BCR-ABL fusion protein (33Nishiyama-Fujita Y. Shimizu T. Sagawa M. Uchida H. Kizaki M. The role of TC-PTP (PTPN2) in modulating sensitivity to imatinib and interferon-α in CML cell line, KT-1 cells.Leuk. Res. 2013; 37 (23759247): 1150-115510.1016/j.leukres.2013.05.008Crossref PubMed Scopus (8) Google Scholar). These studies highlight the important role of PTPN2 in hematopoiesis, inflammation, and immune response. In this work, we show that 1,4-benzoquinone, the prime hematotoxic metabolite of benzene, is an irreversible inhibitor of PTPN2. Kinetic and biochemical analyses using purified human PTPN2 indicated that this irreversible inhibition of the enzyme is mainly due to rapid arylation of its catalytic cysteine by 1,4-benzoquinone. Further studies in cells expressing PTPN2 showed that exposure to 1,4-benzoquinone leads to the irreversible inhibition of the endogenous enzyme with a concomitant overactivation of the STAT1 signaling and subsequent alteration of the expression of STAT1-regulated genes. Altogether, our data provide the first evidence for the alteration of a key hematopoietic and immune signaling pathway by benzene. These findings shed a new light on our understanding of the mechanism by which benzene may induce hematological malignancies. The leukemogenic properties of benzene are known to rely on its bioactivation in the bone marrow into reactive metabolites, in particular 1,4-benzoquinone (1Smith M.T. Zhang L. McHale C.M. Skibola C.F. Rappaport S.M. Benzene, the exposome and future investigations of leukemia etiology.Chem. Biol. Interact. 2011; 192 (21333640): 155-15910.1016/j.cbi.2011.02.010Crossref PubMed Scopus (91) Google Scholar, 4McHale C.M. Zhang L. Lan Q. Vermeulen R. Li G. Hubbard A.E. Porter K.E. Thomas R. Portier C.J. Shen M. Rappaport S.M. Yin S. Smith M.T. Rothman N. Global gene expression profiling of a population exposed to a range of benzene levels.Environ. Health Perspect. 2011; 119 (21147609): 628-63410.1289/ehp.1002546Crossref PubMed Scopus (86) Google Scholar, 14Eastmond D.A. Keshava N. Sonawane B. Lymphohematopoietic cancers induced by chemicals and other agents and their implications for risk evaluation: an overview.Mutat. Res. Rev. Mutat. Res. 2014; 761 (24731989): 40-6410.1016/j.mrrev.2014.04.001Crossref Scopus (28) Google Scholar). This hematotoxic quinone arises in the bone marrow mainly from myeloperoxidase-catalyzed conversions of phenolic metabolites of benzene originating from the liver, mainly phenol (PH) and hydroquinone (HQ) (Fig. 1A) (2Snyder R. Leukemia and benzene.Int. J. Environ. Res. Public Health. 2012; 9 (23066403): 2875-289310.3390/ijerph9082875Crossref PubMed Scopus (144) Google Scholar, 34Mondrala S. Eastmond D.A. Topoisomerase II inhibition by the bioactivated benzene metabolite hydroquinone involves multiple mechanisms.Chem. Biol. Interact. 2010; 184 (20034485): 259-26810.1016/j.cbi.2009.12.023Crossref PubMed Scopus (36) Google Scholar, 35Bolton J.L. Dunlap T. Formation and biological targets of quinones: cytotoxic versus cytoprotective effects.Chem. Res. Toxicol. 2017; 30 (27617882): 13-3710.1021/acs.chemrestox.6b00256Crossref PubMed Scopus (219) Google Scholar). As shown in Fig. 1B, we found that, contrary to the phenolic metabolites of benzene, 1,4-benzoquinone inhibited PTPN2 phosphatase activity (IC50 = 1 μm). Whereas full inhibition of the enzyme was observed with low micromolar concentrations of 1,4-benzoquinone (2 μm), no significant effects were observed with phenol and hydroquinone even at concentrations 2 orders of magnitude higher (200 μm). To confirm that 1,4-benzoquinone inhibits PTPN2, an in vitro myeloperoxidase (MPO) activation system that mimics the bioactivation of hydroquinone into 1,4-benzoquinone in the bone marrow was used as described previously (9Frantz C.E. Chen H. Eastmond D.A. Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites.Environ. Health Perspect. 1996; 104 (9118913): 1319-132310.1289/ehp.961041319Crossref PubMed Scopus (59) Google Scholar, 34Mondrala S. Eastmond D.A. Topoisomerase II inhibition by the bioactivated benzene metabolite hydroquinone involves multiple mechanisms.Chem. Biol. Interact. 2010; 184 (20034485): 259-26810.1016/j.cbi.2009.12.023Crossref PubMed Scopus (36) Google Scholar). In the presence of a functional MPO activation system (MPO, hydroquinone, and H2O2) able to convert hydroquinone into 1,4-benzoquinone, PTPN2 activity was fully inhibited (Fig. 1C). Conversely, in reactions containing inactive MPO, no inhibition of PTPN2 was found (Fig. 1C), thus confirming that this tyrosine phosphatase is sensitive to 1,4-benzoquinone but not the phenolic metabolites of benzene. 1,4-Benzoquinone is known to arylate directly protein thiol groups through Michael addition (35Bolton J.L. Dunlap T. Formation and biological targets of quinones: cytotoxic versus cytoprotective effects.Chem. Res. Toxicol. 2017; 30 (27617882): 13-3710.1021/acs.chemrestox.6b00256Crossref PubMed Scopus (219) Google Scholar, 36Mbiya W. Chipinda I. Siegel P.D. Mhike M. Simoyi R.H. Substituent effects on the reactivity of benzoquinone derivatives with thiols.Chem. Res. Toxicol. 2013; 26 (23237669): 112-12310.1021/tx300417zCrossref PubMed Scopus (19) Google Scholar37Li Y. Jongberg S. Andersen M.L. Davies M.J. Lund M.N. Quinone-induced protein modifications: Kinetic preference for reaction of 1,2-benzoquinones with thiol groups in proteins.Free Radic. Biol. Med. 2016; 97 (27212016): 148-15710.1016/j.freeradbiomed.2016.05.019Crossref PubMed Scopus (80) Google Scholar). This arylating ability of 1,4-benzoquinone is considered as a major mechanism responsible for the toxicological effects of this quinone, in particular in the bone marrow (1Smith M.T. Zhang L. McHale C.M. Skibola C.F. Rappaport S.M. Benzene, the exposome and future investigations of leukemia etiology.Chem. Biol. Interact. 2011; 192 (21333640): 155-15910.1016/j.cbi.2011.02.010Crossref PubMed Scopus (91) Google Scholar, 2Snyder R. Leukemia and benzene.Int. J. Environ. Res. Public Health. 2012; 9 (23066403): 2875-289310.3390/ijerph9082875Crossref PubMed Scopus (144) Google Scholar, 38Rappaport S.M. Waidyanatha S. Yeowell-O'Connell K. Rothman N. Smith M.T. Zhang L. Qu Q. Shore R. Li G. Yin S. Protein adducts as biomarkers of human benzene metabolism.Chem. Biol. Interact. 2005; 153 (15935805): 103-10910.1016/j.cbi.2005.03.014Crossref PubMed Scopus (43) Google Scholar, 39Eastmond D.A. Mondrala S.T. Hasegawa L. Topoisomerase II inhibition by myeloperoxidase-activated hydroquinone: a potential mechanism underlying the genotoxic and carcinogenic effects of benzene.Chem. Biol. Interact. 2005; 153 (15935818): 207-21610.1016/j.cbi.2005.03.024Crossref PubMed Scopus (40) Google Scholar). Exposure of purified PTPN2 to 1,4-benzoquinone led to the covalent arylation of the enzyme as evidenced by the visualization of protein–quinone adducts on nitrocellulose membranes using the quinone-specific nitro blue tetrazolium (NBT) staining (40Paz M.A. Flückiger R. Boak A. Kagan H.M. Gallop P.M. Specific detection of quinoproteins by redox-cycling staining.J. Biol. Chem. 1991; 266 (1702437): 689-692Abstract Full Text PDF PubMed Google Scholar) (Fig. 2A). Moreover, the covalent binding of 1,4-benzoquinone to PTPN2 was accompanied by the concomitant loss of cysteine labeling by fluorescein-iodoacetamide (IAF), thus supporting that 1,4-benzoquinone arylation occurs on cysteine residues of PTPN2 (Fig. 2B). As shown in Fig. 2C, the activity of 1,4-benzoquinone–inhibited PTPN2 could not be recovered by dialysis nor by DTT treatment, further supporting the irreversible covalent nature of the reaction between 1,4-benzoquinone and PTPN2 cysteine residues. As shown in Fig. S1, we found that inhibition of PTPN2 by 1,4-benzoquinone was inhibited by GSH, a major physiological reducing agent known to react with 1,4-benzoquinone (35Bolton J.L. Dunlap T. Formation and biological targets of quinones: cytotoxic versus cytoprotective effects.Chem. Res. Toxicol. 2017; 30 (27617882): 13-3710.1021/acs.chemrestox.6b00256Crossref PubMed Scopus (219) Google Scholar). To further ascertain that inhibition of PTPN2 relies on the arylating ability of 1,4-benzoquinone but not on redox cycling mechanisms (that generate reactive oxygen species), the inhibition assays were carried out in the presence of catalase and/or superoxide dismutase as described previously (41Verrax J. Delvaux M. Beghein N. Taper H. Gallez B. Buc Calderon P. Enhancement of quinone redox cycling by ascorbate induces a caspase-3 independent cell death in human leukaemia cells. An in vitro comparative study.Free Radic. Res. 2005; 39 (16036343): 649-6571" @default.
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• W2956003848 title "Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling" @default.
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