Over-expression of CYP2E1 mRNA and protein: implications of xenobiotic induced damage in patients with de novo acute myeloid leukemia with inv(16)(p13.1q22); CBFβ-MYH11.
Environmental exposure to benzene occurs through cigarette smoke, unleaded gasoline and certain types of plastic. Benzene is converted to hematotoxic metabolites by the hepatic phase-I enzyme CYP2E1, and these metabolites are detoxified by the phase-II enzyme NQO1. The genes encoding these enzymes are highly polymorphic and studies of these polymorphisms have shown different pathogenic and prognostic features in various hematological malignancies. The potential role of different cytochrome p450 metabolizing enzymes in the pathogenesis of acute myeloid leukemia (AML) in an area of active interest. In this study, we demonstrate aberrant CYP2E1 mRNA over-expression by quantitative real-time polymerase chain reaction in 11 cases of de novo AML with inv(16); CBFβ-MYH11. CYP2E1 mRNA levels correlated with CBFβ-MYH11 transcript levels and with bone marrow blast counts in all cases. CYP2E1 over-expression correlated positively with NQO1 mRNA levels (R(2) = 0.934, n = 7). By immunohistochemistry, CYP2E1 protein was more frequently expressed in AML with inv(16) compared with other types of AML (p < 0.001). We obtained serial bone marrow samples from two patients with AML with inv(16) before and after treatment. CYP2E1 mRNA expression levels decreased in parallel with CBFβ-MYH11 transcript levels and blast counts following chemotherapy. In contrast, CYP1A2 transcript levels did not change in either patient. This is the first study to demonstrate concurrent over-expression of CYP2E1 and NQO1 mRNA in AML with inv(16). These findings also suggest that a balance between CYP2E1 and NQO1 may be important in the pathogenesis of AML with inv(16).
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Rkanagal@mdanderson.org
Rashmi
R
Kanagal-Shamanna
Weiqiang
W
Zhao
Saroj
S
Vadhan-Raj
Martin H
MH
Nguyen
Michael H
MH
Fernandez
L Jeffrey
LJ
Medeiros
Carlos E
CE
Bueso-Ramos
D000293:Adolescent; D000328:Adult; D000368:Aged; D001554:Benzene / Q000633:toxicity; D002648:Child; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015262:Xenobiotics / Q000633:toxicity; D055815:Young Adult
C095514:CBFbeta-MYH11 fusion protein; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D015262:Xenobiotics; D019392:Cytochrome P-450 CYP2E1; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D001554:Benzene