Benzene-Induced Leukemogenesis: Irreversible Inhibition of PTPN2 and Subsequent STAT1 Signaling Alteration By the Hematotoxic Metabolite Benzoquinone

Benzene (BZ) is a chemical compound of industrial and toxicological interest classified as a class I human carcinogen. Environmental and occupational exposure to BZ lead to bone marrow malignancies such as leukemia. The leukemogenic effects of BZ relies on its metabolization in bone marrow cells into reactive metabolites, in particular benzoquinone (BQ) that can react with macromolecules (arylation) and/or induce oxidative stress. Although BZ is well recognized as a leukemogenic chemical, most of the key molecular and cellular mechanisms underlying its hematotoxicity are not fully understood.

PTPN2 is a protein tyrosine phosphatase (PTP) mainly expressed in hematopoietic cells and playing a key role in the homeostasis of the hematopoietic system. In particular, this PTP is an important modulator of growth factors and JAK/STAT signaling pathways. Loss of function analyses in patients with mutation/deletion of the PTPN2 gene and knock-out mouse models indicate that PTPN2 acts as a tumor suppressor in haematologic disorders such as leukemia.

We found that BQ, the prime hematotoxic metabolite of BZ, is an irreversible inhibitor of human PTPN2. Kinetic and biochemical analyses using purified PTPN2 indicated that the irreversible inhibition of the enzyme by BQ is mainly due to arylation of its active site cysteine. Exposure of immortalized human hematopoietic cells (Jurkat T and THP-1 lines) to BQ leads to the irreversible inhibition of endogenous PTPN2 activity with a concomitant over activation of JAK/STAT signaling pathway. Irreversible BQ-dependent inhibition of PTPN2 in cells was found to be mainly due to overoxydation of its catalytic cysteine into sulfinic and/or sulfonic forms.

In Vivo experiments conducted in mice confirmed that exposure to BZ leads to irreversible inhibition of PTPN2 in bone marrow and spleen cells.

Our data provide the first mecanistic evidence that irreversible inhibition of PTPN2, a tumor suppressor tyrosine phosphatase, may contribute to benzene-dependent leukemogenesis.