Disruption of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia.
NAD(P)H:quinone oxidoreductase1 (NQO1) is a cytosolic protein that reduces and detoxifies quinones and their derivatives, thus protecting cells against redox cycling and oxidative stress. Disruption of the NQO1 gene in mice caused myeloid hyperplasia of bone marrow and highly significant increases in blood neutrophils, eosinophils, and basophils. NQO1-null mice also showed a decrease in lymphocytes and WBCs as compared with wild-type mice. Various techniques also demonstrated an increase in megakaryocytes without an increase in blood platelets. Histological analysis of liver, kidney, spleen, and thymus did not demonstrate a difference between wild-type and NQO1-null mice or a sign of infection. Blood cultures and urine analysis also did not demonstrate any sign of infection in NQO1-null and wild-type mice. Additional analysis of the bone marrow from NQO1-null mice revealed that loss of NQO1 alters the intracellular redox status because of accumulation of NAD(P)H, cofactors for NQO1. This causes a reduction in the levels of pyridine nucleotides and tumor suppressor proteins p53 and p73, and a decrease in apoptosis. The decrease in apoptosis causes myelogenous hyperplasia in NQO1-null mice. These results demonstrate that NQO1 acts as an endogenous factor in the protection against myelogenous hyperplasia. This is significant because 2-4% of human individuals without known abnormalities, and >25% of individuals with benzene poisoning and acute myelogenic leukemia are homozygous for a mutant allele (P187S) of NQO1 and lack NQO1 protein/activity.
Long
Delwin J
DJ
Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Gaikwad
Amos
A
Multani
Asha
A
Pathak
Sen
S
Montgomery
Charles A
CA
Gonzalez
Frank J
FJ
Jaiswal
Anil K
AK
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002454:Cell Differentiation / Q000235:genetics; D002875:Chromosomes; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D006965:Hyperplasia / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D009196:Myeloproliferative Disorders / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D009249:NADP; D016660:NAD(P)H Dehydrogenase (Quinone)