Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling

摘要: Protein tyrosine phosphatase, nonreceptor type 2 (PTPN2) is mainly expressed in hematopoietic cells, where it negatively regulates growth factor and cytokine signaling. PTPN2 an important regulator of hematopoiesis immune/inflammatory responses, as evidenced by loss-of-function mutations leukemia lymphoma knockout mice studies. Benzene environmental chemical that causes hematological malignancies, its hematotoxicity arises from bioactivation the bone marrow to electrophilic metabolites, notably 1,4-benzoquinone, a major hematotoxic benzene metabolite. Although molecular bases for benzene-induced are not well-understood, has been suggested metabolites alter topoisomerases II function thereby significantly contribute leukemogenesis. However, several studies indicate may also promote leukemogenic process reacting with other targets pathways. Interestingly, alterations cell-signaling pathways, such Janus kinase (JAK)/signal transducer activator transcription (STAT), have proposed malignant blood diseases. We show here 1,4-benzoquinone directly impairs activity. Mechanistic kinetic experiments purified human indicated this impairment results irreversible formation (kinact = 645 m−1·s−1) covalent adduct at catalytic cysteine residue enzyme. Accordingly, cell revealed exposure irreversibly inhibits cellular concomitantly increases phosphorylation STAT1 expression STAT1-regulated genes. Our provide evidence covalently modifies key signaling enzymes, implicating