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Carcinogenesis |
Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030 [D. J. L., A. G., A. K. J.]; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 [A. M., S. P.]; Lexicon Genetics, Woodlands, Texas 77381 [C. A. M.]; and National Cancer Institute, Bethesda, Maryland 20892 [F. J. G.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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-glutamylcysteine synthetase, which plays a key role in the regulation of glutathione metabolism (1, 2, 3, 4)
. Therefore, the coordinated induction of these genes, including NQO1, provides the necessary cellular protection against free radical damage and oxidative stress. Two to four percent 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 (5, 6, 7, 8) . These individuals are deficient in NQO1 protein and activity (5, 6, 7, 8) . By use of homologous recombination in embryonic stem cells, exon 6 was replaced with a neomycin cassette to generate NQO1-null mice (9) . Neither NQO1 activity nor protein was detected in the various tissues examined (9) . Mice lacking NQO1 gene expression accumulated lower amounts of abdominal fat and showed increased sensitivity to menadione-induced hepatic toxicity as compared with wild-type mice (9 , 10) .
In the present study, we demonstrate that loss of NQO1 causes myeloid hyperplasia of bone marrow and significant increase in blood neutrophils, eosinophils, and basophils in NQO1-null mice. We also demonstrate that accumulation of NAD(P)H (cofactors for NQO1) leads to a decrease in pyridine nucleotides, and tumor suppressor proteins p53 and p73 in the bone marrow of NQO1-null mice. This results in a significant decrease in apoptosis and myelogenous hyperplasia of bone marrow.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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The NQO1-null mice were found to be normal in appearance and showed no discernible difference in their development or in their behavior compared with their wild-type NQO1+/+ litter-mates (9) . This was true for both male and female mice. In addition, the NQO1-null mice appeared to have normal reproductive capacity when compared with wild-type mice.
Peripheral Blood Analysis.
Eleventh generation of NQO1-null and wild-type mice were anesthetized with isoflurane (Vedco, St. Joseph, MO) followed by i.p. injections of a combination anesthetic (2.14 mg ketamine, 0.43 mg xylazine, and 70 µg acepromazine). The animals were opened and 0.25 cc of blood was withdrawn from the heart with a 22-gauge needle. The syringes were coated with 0.5 M EDTA to prevent coagulation. The blood was immediately placed into EDTA coated tubes (Microtainer; Fisher Scientific, Houston, TX) and thoroughly mixed. The blood samples were analyzed by a Technicon H1 analyzer.
Bone Marrow NQO1 Protein and Activity.
The wild-type and NQO1-null mice from eleventh generation were sacrificed and their femurs removed. The bones were cut, and marrow flushed out and homogenized in a buffer containing 250 mM sucrose, 1 mM EDTA, and cytosol prepared by standard techniques (9)
. The cytosolic proteins (75µg) were run on 10% SDS-PAGE, transferred to ECL nitrocellulose membranes and probed with polyclonal antibodies against NQO1. The cytosolic fractions were also analyzed for NQO1 activity by procedures described previously (9)
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Analysis of Bone Marrow Cytospins.
NQO1-null and wild-type mice were euthanized. The femurs were surgically removed from the animals. The heads of each femur were removed, and the bone was then flushed with 
1 ml of PBS containing 1 mM EDTA. The volume flushed from each bone was increased to 3 ml with PBS. The solution was mixed, and 150 µl were used for each cytospin preparation. The samples were spun onto slides using a Cyto-Tek Centrifuge (Sakura Scientific, Torrance, CA) at 1600 rpm for 10 min. Differential staining was done on the cytospin preparations using the HEMA 3 stain set from Fisher Scientific (Houston, TX). Additional slides containing bone marrow cells were fixed in 95% ethanol and stained with an antihuman myeloperoxidase antibody (DAKO, Glostrup, Denmark). The secondary antibodies and the development kit were obtained from Vector Laboratories (Burlingame, CA). The slides were stained according to the manufacture’s protocol.
Histology.
NQO1-null and wild-type mice were euthanized, and the femurs/sternums were surgically removed. The bones were placed in 10% neutral buffered formalin (Fischer Scientific, Houston, TX) for 24 h. After this time period, the bones were decalcified in TBD-2 Decalcifier (23% formic acid +9% sodium citrate; Shandon Lipshaw, Pittsburgh, PA) for 24 h. The tissues were then embedded in paraffin and cut into 4-µm sections. The sections were placed onto slides and stained with H&E (Richard-Allan Scientific, Kalamazoo, MI). In addition to bone marrow, histological analysis was also performed on the liver, kidney, spleen, and thymus of wild-type and NQO1-null mice. These tissues were fixed in formalin, embedded in paraffin, cut into sections, and stained with H&E by standard procedures.
Cytogenetic Preparations.
The wild-type and NQO1-/- male and female mice were injected i.p. with 0.2 ml of Colcemid (2.0 mg/ml stock solution) 1 h before killing. Bone marrow was aspirated in a hypotonic solution (0.075 M KCl) with the help of a syringe fitted with a 25-gauge needle. Cell clumps were broken into single-cell suspension by mild vortexing. Cells were suspended in KCl solution for 15–20 min at room temperature, fixed in acetic acid:methanol (1:3 by volume) and finally dropped onto glass slides for air-dried preparations. G banding was performed after standard laboratory procedures (10)
. Banded chromosomes were classified following the standard nomenclature of the Committee on Standardized Genetic Nomenclature for Mice (11)
. An average of 15–20 G banded metaphases was photographed and complete karyotypes prepared from each animal using a Genetiscan (Perceptive System, Inc., Houston, TX). An additional 10–15 conventionally Giemsa-stained metaphase spreads from each animal were evaluated for any chromatid or chromosome-type aberrations and for the determination of model chromosome number.
Menadione Treatment.
Menadione (Sigma Chemical Company, St. Louis, MO) was dissolved in DMSO. Menadione (5 mg/kg body weight) was administered intraperitonialy once every day for 3 days to wild-type and NQO1-null mice. Control mice received DMSO alone. The blood was drawn 24 h after the last injection and analyzed. In related experiments, the mice were euthanized, and bone marrow was collected and analyzed by procedures as described above.
NAD(P)H:NAD(P) Ratio in Bone Marrow.
The following procedure was used to collect and process the tissue for determination of NAD(P) and NAD(P)H because of sensitivity of these molecules. The bone marrow was surgically removed while the mice were under anesthesia to avoid changes in the levels of the pyridine nucleotides. The bone marrow was then instantly placed in liquid nitrogen (12)
. While frozen, the ends of the bone were cut using a surgical blade, and while the marrow was thawing, it was flushed by using the solution containing 200 mM KCN, 1 mM bathophenanthroline, and 60 mM KOH. The pyridines were extracted with chloroform and analyzed from these tissues by procedures as described previously (13)
. Briefly, the homogenate was extracted rapidly with chloroform several times until minimal precipitate was observed at the interface of the buffer and chloroform. The supernatant was then passed through a 0.45 µm Ultrafree-MC filtration device (Millipore, Bedford, MA) by centrifuging at 5000 rpm for 10 min at 4°C. This removed the residual DNA/protein and also served as a filter before the samples are loaded onto the HPLC column. The pyridine nucleotides were separated, analyzed, and quantitated using a C18 chromatography column (Waters Corp., Milford, MA) and HPLC (Waters Corp.). The mobile phase consisted of 50-mM potassium phosphate buffer (pH 7.05):acetonitrile (97:3) as suggested by the manufacturer.
Analysis of PCNA, Pu-1, C/EBP
, p53, and p73 in Bone Marrow.
Wild-type and NQO1-null mice were sacrificed, and femurs removed by surgery and quickly frozen in liquid nitrogen. The ends of the bone were then removed under frozen conditions and flushed quickly with a ice-cold buffer containing 50 mM Tris-Cl (pH 7.5), 150 mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 0.5% Triton X-100, and a mixture of protease inhibitors including 1 mM phenylmethylsulfonyl fluoride, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 1 µg/ml each of pepstatin, aprotinin, leupeptin, benzamidine-Cl, and antipain (all from Sigma Chemical Co.). Various bone marrow protein samples (75 µg) were separated on 10% SDS-PAGE, blotted on the ECL-membranes, and probed with antibodies against PCNA (PharMingen, San Diego, CA), myeloid cell differentiation factors Pu.1 (PharMingen), C/EBP (a gift from Dr. Darlington Gretchen, Baylor College of Medicine, Houston, TX), tumor suppressor proteins p53 (ICN Biochemicals, Costa Mesa CA), p73 (a gift from Dr. Dennis Roop, Baylor College of Medicine), and tubulin (Sigma Chemical Co.). Western blots were developed with ECL (Amersham Pharmacia Biotech, Buckinghamshire, England) reagents by the procedures suggested by the manufacturer.
Apoptosis.
Apoptosis was measured by using the annexin V-FITC detection kit (PharMingen). NQO1-null and wild-type mice were anesthetized, and bone was surgically removed. The bone marrow was flushed gently with sterile PBS. After two PBS washes, the cells were suspended in the annexin V- FITC binding buffer to a concentration of 1 x 106 cells/ml. Assay for the determination of apoptotic cells was essentially performed as described by the manufacturer and measured using Coulter (R) Epics XL-MCL Flow Cytometer (Beckman-Coulter Co, Miami, FL).
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RESULTS AND DISCUSSION |
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). Mice lacking NQO1 gene expression showed no detectable phenotype and were indistinguishable from the wild-type mice. The blood, urine, and serology analysis of wild-type and NQO1-/- mice did not show any sign of infection (data not shown).
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; Fig. 1C
). NQO1-null mice had an increase in the number of segmented neutrophils (Fig. 1C)
. The number of platelets, RBCs, and monocytes showed no significant changes, whereas the WBCs and lymphocytes were lower in the NQO1-null mice. The decrease in the number of lymphocytes was significant, whereas the decrease in the total WBC count was marginal. The various changes were observed in 6-week-old mice, yet they were more prominent in 24-week old mice. Analysis of the bone marrow from NQO1-null mice revealed a significant increase in myeloid cells (Table 2
; Fig. 2
). This observation, along with the changes in the peripheral blood cell counts, demonstrates that loss of NQO1 results in myeloid cell hyperplasia, presumably caused by a shift from the lymphoid to myeloid lineage. The decrease in the total WBC counts may be caused by the significant reduction in lymphocytes. Interestingly, the bone marrow from NQO1-null mice also showed a significant increase in the number of megakaryocytes (Fig. 3)
. However, the increase in megakaryocytes did not cause an increase in the number of peripheral blood platelets (Table 1)
. The increase in megakaryocytes, without a corresponding change in peripheral blood platelets, suggests that the megakaryocytes may be undergoing apoptosis. This is a possibility because some of the megakaryocytes in NQO1-null mice appeared dysplastic (Fig. 3)
. Histological analysis of liver, kidney, spleen, and thymus did not reveal a difference between wild-type and NQO1-null mice (data not shown). The histological analysis of various tissues also did not show any sign of infection. This was also evident from the observation that total WBC count was normal in the blood of NQO1-null and wild-type mice (Table 1)
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. However, a few metaphases in both groups were tetraploid with a chromosome number 78–80. From these observations we conclude that NQO1-null mice did not contain any mitotic catastrophe, not even in chromosome 2, which is heavily involved in radiation-induced myeloid leukemia (14)
. These results were not surprising, because NQO1-null mice are preconditioned but do not have myeloid leukemia. However, NQO1-null mice are susceptible, and expected to develop myeloid leukemia and associated chromosomal aberrations if exposed to radiations and/or leukemia-causing chemicals.
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NQO1-null and wild-type mice were given i.p. injections of oxidative stress-causing agent menadione, and analyzed for a menadione/oxidative stress effect on hepatic toxicity and hematopoiesis. The treatment of wild-type and NQO1-null mice with menadione resulted in hepatic damage as evident from elevation of hepatotoxicity markers aspartate aminotransferase and alanine aminotransferase in the serum of these mice (data not shown; Ref. 9
). The hepatic damage was significantly more in NQO1-null mice, because of the absence of NQO1, which detoxifies menadione. The mice livers, rich in cytochrome P450 reductase, catalyzes metabolic activation of menadione, leading to the generation of electrophiles and reactive oxygen species that cause hepatic damage. The NQO1 enzyme in wild-type mice competes with P450 reductase, and catalyzes two-electron reduction and detoxification of menadione, thus leading to protection against menadione-induced hepatic damage. On the other hand, the NQO1-null mice deficient in NQO1 and its protection against menadione demonstrated increased hepatic damage as compared with wild-type mice. Interestingly, no significant changes were observed between the untreated and menadione-treated wild-type and NQO1-null peripheral blood (Table 3)
or bone marrow (data not shown). This may be related to lower amounts of one-electron reducing enzyme cytochrome P450 reductase in the bone marrow as compared with liver. These results suggested that oxidative stress is not a major factor underlying the myelogenous hyperplasia in the NQO1-null animals. However, it is not clear whether endogenous quinones and/or dietary quinones contribute to the myelogenous hyperplasia and increase in megakaryocytes.
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. In addition, the absolute levels of pyridine nucleotides (NAD(P)H and NAD(P)) were lower in NQO1-null mice presumably because the accumulation of NAD(P)H causes feedback inhibition of the pentose phosphate pathway, which provides ribose for the synthesis of NAD(P) (Fig. 5)
. These results in bone marrow were also supported by similar observations in the liver and kidney of NQO1-null mice as compared with wild-type mice (15)
. The liver and kidney of NQO1-null mice showed an increase in the NAD(P)H:NAD(P) ratio and decreased pyridine nucleotide levels (15)
. These led to alterations in the intracellular redox status and significant alterations in cellular metabolism of carbohydrates and fats (15)
. The NQO1-null mice showed lower blood levels of glucose, no change in insulin, and higher levels of triglycerides, ß-hydroxy butyrate, pyruvate, lactate, and glucagon as compared with wild-type mice. An insulin tolerance test demonstrated that the NQO1-null mice have a mild insulin tolerance. The NQO1-null mice livers also showed significantly higher levels of triglycerides, lactate, pyruvate, and glucose. The liver glycogen reserve was found decreased in NQO1-null mice as compared with wild-type mice. The alterations in metabolism because of redox changes also resulted in a significant reduction in the amount of abdominal adipose tissue.
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. Therefore, the contribution of cellular proliferation in myeloid cell hyperplasia of bone marrow in NQO1-null mice may be limited to none. Similarly, the two markers (C/EBP and Pu-1) of myeloid cell differentiation also showed more or less no change between bone marrow of wild-type and NQO1-null mice indicating that differentiation processes may be functioning properly in bone marrow of NQO1-null mice (Fig. 6
; data shown for Pu-1). This was also supported by the observations that neutrophils, eosinophils, and basophils all appeared well differentiated in peripheral blood of NQO1-null mice (Fig. 1)
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. The decrease in apoptosis in NQO1-null mice was significant (P > 0.01). These observations are in agreement with a recent report showing a decrease in the levels of p53 and apoptosis in cells that had been treated with an inhibitor (dicoumarol) of NQO1 (17)
. This report demonstrated that the decrease in p53 levels was through the proteasomal degradation pathway. Therefore, it is likely that the decreased levels of NAD(P), in NQO1-null bone marrow, results in degradation of p53, p73, and other yet unknown growth regulatory factors. The partial loss of p53 and p73 may lead to decreased apoptosis of myeloid cells in the bone marrow of NQO1-null mice. The role of NAD in stabilizing p53 is also suggested by other reports, which demonstrate decreased basal levels of p53 in human breast, skin, and lung cells grown in nicotinamide-deficient medium (18
, 19)
. A decrease in apoptosis may account for the increase in myeloid cells in the NQO1-null bone marrow. The present studies using total bone marrow did not demonstrate a significant role for cellular proliferation and differentiation in NQO1-/- mice as compared with wild-type mice. However, this needs to be confirmed by additional studies with more factors and markers, and isolated myeloid cells. Similarly, the roles of cellular proliferation, differentiation, and apoptosis in the increase of megakaryocytes in the NQO1-null bone marrow without a change in blood platelets levels also remain to be investigated.
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In addition to the increase in myeloid cells and megakaryocytes, the NQO1-null mice also exhibit a significant decrease in lymphocytes and a marginal decrease in WBCs. The marginally decreased WBC count may be because of a decrease in lymphocytes. However, it is not known whether the decrease in lymphocytes is directly related to the loss of NQO1. It is also possible that the increase in myeloid cells signals the down-regulation of lymphocytes to keep the total number of WBCs relatively constant. However, it is noteworthy that the low or null NQO1 P187S allele was found to be associated with chromosomal translocations and inversions in AML patients (31) .
In conclusion, disruption of the NQO1 gene in mice causes myeloid hyperplasia in the bone marrow and an increase in megakaryocytes. Alterations in the NADH:NAD ratio and lower NAD levels lead to a decrease in the levels of the tumor suppressor proteins p53, p73, and apoptosis. These changes contribute to the increase in myeloid cells/megakaryocytes and have the potential to lead to AML in NQO1-null mice. This consequence of NQO1 disruption is in addition to its role in detoxification of redox cycling quinones and protection against their toxicity. These studies also suggest that human individuals lacking the expression of the NQO1 gene, caused by mutations such as the P187S, may be at higher risk for developing AMLs. The NQO1-null mice have great potential to develop into a model to study acute leukemias and antiacute leukemia chemotherapy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by NIH Grant RO1 ES07943. 
2 Both authors contributed equally to this work.
3 To whom requests for reprints should be addressed, at Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-7691; Fax: (713) 798-3145; E-mail: ajaiswal{at}bcm.tmc.edu
4 The abbreviations used are: NQO1, NADPH:quinone oxidoreductase 1 or DT diaphorase; ECL, enhanced chemiluminescence; HPLC, high-performance liquid chromatography; PCNA, proliferating cell nuclear antigen; C/EBP, CAAT/enhancer binding protein; AML, acute myelogenous leukemia; ES, embryonic stem; KOH, potassium hydroxide; KCN, potassium cyanide.
Received 10/16/01. Accepted 4/ 2/02.
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T polymorphism in the NAD(P)H:Quinone Oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. Blood, 94: 803-807, 1999.This article has been cited by other articles:
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S. Kannan and A. K. Jaiswal Low and High Dose UVB Regulation of Transcription Factor NF-E2-Related Factor 2. Cancer Res., September 1, 2006; 66(17): 8421 - 8429. [Abstract] [Full Text] [PDF]
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K. S. Ahn, G. Sethi, A. K. Jain, A. K. Jaiswal, and B. B. Aggarwal Genetic Deletion of NAD(P)H:Quinone Oxidoreductase 1 Abrogates Activation of Nuclear Factor-{kappa}B, I{kappa}B{alpha} Kinase, c-Jun N-terminal Kinase, Akt, p38, and p44/42 Mitogen-activated Protein Kinases and Potentiates Apoptosis J. Biol. Chem., July 21, 2006; 281(29): 19798 - 19808. [Abstract] [Full Text] [PDF]
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K. Iskander, A. Gaikwad, M. Paquet, D. J. Long II, C. Brayton, R. Barrios, and A. K. Jaiswal Lower Induction of p53 and Decreased Apoptosis in NQO1-Null Mice Lead to Increased Sensitivity to Chemical-Induced Skin Carcinogenesis Cancer Res., March 15, 2005; 65(6): 2054 - 2058. [Abstract] [Full Text] [PDF]
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D. A. Bloom and A. K. Jaiswal Phosphorylation of Nrf2 at Ser40 by Protein Kinase C in Response to Antioxidants Leads to the Release of Nrf2 from INrf2, but Is Not Required for Nrf2 Stabilization/Accumulation in the Nucleus and Transcriptional Activation of Antioxidant Response Element-mediated NAD(P)H:Quinone Oxidoreductase-1 Gene Expression J. Biol. Chem., November 7, 2003; 278(45): 44675 - 44682. [Abstract] [Full Text] [PDF]
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D. J. Long II, K. Iskander, A. Gaikwad, M. Arin, D. R. Roop, R. Knox, R. Barrios, and A. K. Jaiswal Disruption of Dihydronicotinamide Riboside:Quinone Oxidoreductase 2 (NQO2) Leads to Myeloid Hyperplasia of Bone Marrow and Decreased Sensitivity to Menadione Toxicity J. Biol. Chem., November 22, 2002; 277(48): 46131 - 46139. [Abstract] [Full Text] [PDF]
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