A novel role of CYP2E1 in human megakaryocyte development.
Cytochrome P450 2E1 (CYP2E1) has active roles in bioconversion and biotransformation in humans. Although predominantly present in hepatocytes, CYP2E1 has also been found in hematopoietic stem cells and subtypes of acute myeloid leukemia with unknown clinical significance except for the metabolism of anti-fungal drugs. In the present study, we demonstrated a novel role of CYP2E1 inducing megakaryocyte development in human hematopoietic stem cells and leukemia bipotent K562 cells. CYP2E1 was induced by phorbol-12-myristate-13-acetate in dose-dependent manner in K562 cells as well as in hematopoietic stem cells by thrombopoietin, and ingenol 3,20-dibenzoate (IDB), respectively. Overexpression of CYP2E1 was positively correlated with megakaryocytes and in megakaryocyte maturation. In addition, plasmid-driven expression of CYP2E1 in K562 cells led to morphological transformation of leukemic blasts to pro- and mature megakaryocytes. In contrast, knockout of CYP2E1 by specific interfering RNA diverted these cells to erythroid differentiation. Finally, treatment of K562 cells by a free radical scavenger, N-acetyl L-lysine significantly inhibited CYP2E1 and megakaryocyte differentiation. In summary, our data demonstrated that activation of CYP2E1 and reactive oxygen species signaling promotes megakaryocyte development.
Pathology Core Facility, Department of Pathology, The Ohio State University, Columbus, OH, U.S.A.
Yan
Y
Tang
Pathology Core Facility, Department of Pathology, The Ohio State University, Columbus, OH, U.S.A.
Guojuan
G
Zhang
Pathology Core Facility, Department of Pathology, The Ohio State University, Columbus, OH, U.S.A.
Maureen
M
Baird
Nichols Institute, Quest Diagnostics, San Juan Capistrano, CA, U.S.A.
Frederick
F
Racke
Pathology Core Facility, Department of Pathology, The Ohio State University, Columbus, OH, U.S.A. weiqiang.zhao@osumc.edu.
Weiqiang
W
Zhao
D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D034061:Thrombopoiesis / Q000235:genetics
D002070:Butadienes; D009570:Nitriles; D017382:Reactive Oxygen Species; C113580:U 0126; D004921:Erythropoietin; D019392:Cytochrome P-450 CYP2E1
CYP2E1; ROS; development; megakaryocyte