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[Cancer Research 60, 4256-4261, August 1, 2000]
© 2000 American Association for Cancer Research

Tumor Biology

The Oncogenic Properties of the HMG-I Gene Family1

Lisa J. Wood, Joseph F. Maher2, Tracie E. Bunton3 and Linda M. S. Resar4

Hematology Division (L. J. W., L. M. S. R.) and Departments of Pediatrics (L. J. W., L. M. S. R.), Molecular Biology and Genetics (J. F. M.), Comparative Medicine (T. E. B.), and Oncology (L. M. S. R.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The HMG-I gene family encodes high mobility group proteins originally identified as nonhistone chromosomal binding proteins. HMG-I and -Y proteins are alternatively spliced products of the same mRNA; HMG-C is encoded by a separate gene. The HMG-I proteins function as architectural chromatin-binding proteins that bind to the narrow groove of AT-rich regions in double-stranded DNA. Recent studies indicate an important role for HMG-I proteins in regulating gene expression. Moreover, increased expression of the HMG-I, -Y, and -C proteins correlates with cellular proliferation and neoplastic transformation in several cell types and human cancers. Previous work from our laboratory has shown that HMG-I is a direct c-Myc target gene that is involved in Myc-mediated neoplastic transformation. In this report, we show that increased expression of HMG-Y or -C leads to transformation with anchorage-independent cell growth in two experimental cell lines in a manner similar to that of HMG-I or c-Myc. Moreover, Rat 1a cells overexpressing HMG-Y or -C form tumors in nude mice analogous to Rat 1a cells overexpressing HMG-I or c-Myc. Distant metastases developed in animals injected with cells overexpressing HMG-I or -C. Our findings suggest that the HMG-I gene family is involved in neoplastic transformation and may represent a new family of oncogenes important in the pathogenesis of several human cancers.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The HMG-I gene family encodes the HMG-I, -Y, and -C proteins, which were originally identified as basic, nonhistone, chromosomal binding proteins (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) . HMG-I and -Y proteins are encoded by alternately spliced products of the same mRNA and differ by 11 internal amino acids (1, 2, 3, 4, 5, 6, 7) ; HMG-C is encoded by a separate gene (8, 9, 10, 11, 12) . Recent studies indicate an important role for HMG-I proteins in regulating gene expression (13, 14, 15, 16, 17, 18, 19, 20, 21) . Specifically, HMG-I/Y relieves histone H1-mediated repression of transcription (19, 20, 21) . Moreover, HMG-I/Y is essential for the viral induction of the IFN-ß gene (13, 14, 15, 16, 17) . The HMG-I proteins contain three DNA-binding domains called AT hooks that enable the proteins to bind to the AT-rich stretches of chromosomal DNA in the minor groove (22, 23, 24, 25) . Because these proteins alter the conformation of DNA, they have been termed architectural transcription factors.

Expression of HMG-I/Y also correlates with rapidly proliferating mammalian tissues as well as neoplastic transformation (7 , 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) . In fibroblasts stimulated by serum or growth factors, HMG-I/Y expression follows that of c-myc, with peak expression at 7.5–20 h (34 , 39) . Elevated expression of HMG-I/Y proteins has been observed in several mammalian cancers, including high grade human prostatic cancer (36, 37, 38) and malignant thyroid cancer in rats and humans (27, 28, 29, 30, 31, 32, 33) . Elevated HMG-I/Y expression is also associated with the ability of rat prostatic cell lines to metastasize and has been proposed as a possible diagnostic marker for the metastatic potential of prostatic cancer cells in humans (36) . In addition, a correlation between expression of HMG-I/Y and progressive transformation in mouse mammary epithelial cells has been reported (35) . HMG-I/Y is located on the short arm of chromosome 6, in a region known to be involved in rearrangements, translocations, and other abnormalities correlated with human cancer (4, 5, 6) . Moreover, previous work from our laboratory has shown that HMG-I/Y is a direct c-Myc target involved in Myc-mediated transformation (40 , 41) . In addition, we have shown that increased expression of HMG-I leads to the neoplastic transformation of both Rat 1a cells and CB33 cells (41) . Rat 1a cells overexpressing HMG-I also form tumors in nude mice (41) .

The HMG-C protein has been implicated in the pathogenesis of a variety of benign, solid human tumors (42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62) . Specifically, the HMG-C AT hooks have been identified in chimeric proteins associated with lipomas and other benign, mesenchymal tumors (42, 43, 44, 45, 46, 47, 48 , 55 , 60) . These chimeras are thought to function by binding to DNA via the AT hooks and altering gene expression possibly through the potential transcriptional regulatory domains acquired in the rearrangement (3 , 7 , 43) . HMG-C chimeras observed in lipomas as well as truncated HMG-C that contains the three DNA-binding domains induce neoplastic transformation in NIH3T3 murine fibroblasts (63) . In addition, the truncated HMG-C gene in transgenic mice induced gigantism and lipomatosis (64) . Interestingly, the HMG-C knockout mouse displayed a pygmy phenotype, further suggesting a role for this HMG-I protein in regulating cell growth (65) . More recently, increased expression of HMG-C was identified in a significant percentage of malignant, primary human breast epithelial tumors, which further implies a possible role for HMG-C in the pathogenesis of malignant tumors as well as benign tumors (51) .

To better understand the potential role of the HMG-I gene products in cell growth and neoplasia, we have been studying the oncogenic properties of the HMG-Y and HMG-C proteins and compared their transformation capabilities with those of HMG-I and c-Myc. In this paper, we report that two cell lines overexpressing HMG-Y or -C undergo transformation and exhibit anchorage-independent cell growth in soft agar in a manner analogous to that of HMG-I (41) or c-Myc (66) . Moreover, Rat 1a cells overexpressing HMG -Y or -C form tumors in nude mice as we previously described for Rat 1a cells overexpressing HMG-I (41) . Distant metastases formed in mice injected with cells with ectopic expression of HMG-I or -C. Our findings suggest that HMG-I genes contribute to malignant transformation and may represent a new family of oncogenes important in the pathogenesis of several human malignancies.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cell Culture and Transfection.
The Rat 1a cells used for stable cell lines were maintained as previously described (67) . Rat 1a cells were transfected with plasmids expressing HMG-I (pSG5-HMG-I; 5 µg) and pBABE-puro (1 µg) for puromycin resistance (68) with the use of lipofectin as described by the manufacturer (Life Technologies, Inc.). Polyclonal, pooled, resistant cell lines were selected in media containing puromycin (0.75 µg/ml). For Rat 1a cell lines, transfections were repeated in at least two separate experiments. Polyclonal, selected cells from each transfection experiment were analyzed in soft agar two to three times. CB33 cells, a human lymphoid cell line, were maintained as previously described (67 , 69, 70) and transfected with Effectine (Qiagen) according to the manufacturer’s directions. Transfected cells were selected in media containing Geneticin (Life Technologies, Inc.) at 800 µg/ml as previously described (67) . The polyclonal CB33-Myc (67 , 69, 70) and CB33-HMG-I (41) cells have been previously described. Polyclonal CB33-HMG-Y and CB33-HMG-C cells were selected from a single transfection experiment and analyzed in soft agar at least twice.

Plasmids.
pSG5-HMG-I, pSG5-HMG-Y, and pSG5-HMG-C were made by excision from pBS-HMG-I, pBS-HMG-Y, or pBS-HMG-C, respectively (18) , using HincII and BamHI restriction and ligation to pSG5. Before ligation, pSG5 (Stratagene) underwent restriction digestion with EcoRI, Klenow treatment, and subsequent restriction with BamHI.

PHBoNeo-HMG-I, -Y, and-C were made by excision from pBS-HMG-I, pBS-HMG-Y, or pBS-HMG-C, respectively (18) , with the use of HindIII and NotI and ligated at the same restriction sites in pHBoCMVneo (67) .

Soft Agar Assay.
The soft agar with Rat 1a cells assay was performed as previously described (67) except 5 x 104 Rat 1a cells were suspended in 8 ml of 0.3% agarose and poured onto a 10-ml 0.7% agarose bed in 100-mm tissue culture dishes. Colonies >100 µm were counted after 3–4 weeks. The soft agar assay with CB33 cells was also performed as described (67) except that 1 x 105 cells were suspended in 8 ml of 0.3% agarose. Colonies >1 mm were counted after 3–4 weeks.

Cellular Growth Rates.
The growth rates of the Rat 1a and CB33 cells were determined as previously described (67) . Cells were seeded at 1 x 104 into 10-cm tissue culture dishes. Duplicate dishes were harvested every 24 h for 3 days, and the cells were counted. CB33 cells were seeded at 5 x 105 into 10-cm tissue culture dishes, harvested, and counted as described above.

Tumorigenicity Assays.
Tumorigenicity assays were performed as previously described (71) , but with the following modifications. Rat 1a cells (1 x 107) were suspended in 200 µl of serum-free DMEM and injected s.c. into 6- to 8-week-old athymic nude mice (Ncr-nu mice, National Cancer Institute). Animals were monitored at periodic intervals for the appearance of tumors up to 50–55 days after injection.

Tumor Pathological Examination.
Pathological examination of the tumors was conducted after tumors were fixed by immersion in Bouin’s fixative. Tissues were routinely processed for paraffin embedment, sectioned at 5.0 µm, and stained with H&E.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Rat 1a Cells with Increased HMG-I, -Y, or -C Expression Form Transformed Colonies in Soft Agar.
Because increased expression of HMG-I genes is correlated with cell growth and neoplastic transformation, we hypothesized that HMG-I proteins may participate in neoplastic transformation. Previous work from our laboratory has shown that the HMG-I/Y gene is a c-Myc target (40 , 41) . In addition, the HMG-I protein has several oncogenic properties (40 , 41) . Specifically, ectopic expression of HMG-I leads to the neoplastic transformation of Rat 1a fibroblasts and CB33 cells (41) . Rat 1a cells with increased HMG-I proteins are tumorigenic in nude mice (41) . Finally, decreasing HMG-I protein in Burkitt’s cells inhibited transformation (41) . To explore the potential role of HMG-Y and -C in neoplastic transformation, we constructed polyclonal Rat 1a cell lines overexpressing HMG-Y or -C to determine whether ectopic expression of these proteins leads to transformation in Rat 1a cells. Rat 1a cells overexpressing HMG-Y or -C formed colonies in soft agar in a manner similar to that of Rat1a-HMG-I cells (41) and Rat 1a-myc cells (66) . Both the number of colonies and the size of the foci were similar in the Rat 1a-HMG-I (41) , -Y, and -C cells and Rat 1a-myc cells (66) , suggesting that all three HMG-I proteins have oncogenic properties similar to those of c-Myc in these cells (Fig. 1 and BCitation ).



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  		Fig. 1. Rat 1a cells overexpressing HMG-I, -Y, and -C form colonies in the soft agar assay. In A, Rat 1a cells overexpressing HMG-Y (Rat 1a-HMG-Y), HMG-C (Rat 1a-HMG-C), control Rat 1a cells transfected with the pSG5 vector alone (Rat 1a-Control), positive control Rat 1a cells overexpressing Myc (Rat 1a-Myc; Ref. 66 ), and positive control Rat1a cells overexpressing HMG-I (Rat 1a-HMG-I; Ref. 41 ), were subjected to analysis in the soft agar assay. Rat 1a-HMG-I (41) , -Y, and -C cells formed colonies capable of anchorage-independent cell growth in the soft agar assay like Rat 1a-myc cells (41 , 66) . Bar, 100 µm. In B, the number of colonies formed by the Rat 1a-HMG-I (41) , Rat 1a-HMG-Y, Rat 1a HMG-C, and Rat 1a-myc cells were similar. Transfections were performed in duplicate, and the results are taken from two separate experiments. {blacksquare}, mean from two different experiments; bars, SD. In C, the Rat 1a-HMG cells overexpress the appropriate HMG-I protein. Western analysis showing that the Rat 1a-HMG-Y, and Rat 1a-HMG-C cells overexpress the HMG-Y and HMG-C protein, respectively, compared with control Rat 1a cells transfected with pSG5 vector alone. Lanes 1–3 were blotted with the HMG-I/Y antibody as well as a ß-actin antibody to control for sample loading; Lanes 4 and 5 were blotted with the HMG-C antibody. D, cell growth rates of the Rat 1a cell lines. This experiment was performed with duplicate plates and repeated twice. Bars, SD from a representative experiment. All Rat 1a cell lines grow at similar rates.

 
Western analysis of the Rat 1a cell lines transfected with a plasmid expressing HMG-Y and -C compared with the Rat 1a cells transfected with pSG5 control vector alone shows that the Rat 1a-HMG-Y and -C cells overexpress HMG-Y and -C protein, respectively (Fig. 1CCitation ). To determine whether all of the Rat 1a cell lines grow similarly in tissue culture, we performed growth curves for all of the stable cell lines. All cell lines grew at a similar rate, indicating that the transformed phenotype of the Rat 1a cells overexpressing the HMG-I proteins was not a result of an increased growth rate (Fig. 1DCitation ).

CB33 Cells with Ectopic Expression of HMG-I Proteins Also Exhibit Anchorage-independent Cell Growth in Soft Agar.
To further explore the oncogenic properties of HMG-Y and -C, CB33 cells were also transfected with a plasmids expressing HMG-Y or -C. CB33 cells are human lymphoid cells that are capable of transformation by overexpression of c-Myc (67 , 69 , 70) or HMG-I (41) . We observed that CB33-HMG-Y and CB33-HMG-C cells also formed transformed foci with anchorage-independent cell growth in the soft agar assay like CB33-HMG-I cells (41) and CB33-Myc (Refs. 67 , 69 , and 70 ; Fig. 2 and BCitation ). Western analysis shows that HMG-Y or -C is overexpressed in the CB33 cells (Fig. 2CCitation ). All CB33 cell lines also grow at a similar rate, indicating that the transformed phenotype observed in the CB33-HMG-Y or -C cells is not a result of an increased growth rate (Fig. 2DCitation ). Thus, our results show that HMG-I, -Y or -C have similar transforming activity in two different experimental cell lines, namely, Rat 1a and CB33 cells.



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  		Fig. 2. CB33 cells overexpressing HMG-I, -Y, and -C form colonies in the soft agar assay. In A, CB33 cells overexpressing HMG-Y (Rat 1a-HMG-Y), HMG-C (Rat 1a-HMG-C), control CB33 cells transfected with the vector alone (CB33-Control), or positive control CB33-myc cells (67 , 69 , 70) , and positive control CB33-HMG-I cells (41) were subjected to analysis in the soft agar assay. CB33-HMG-Y, and -C cells formed colonies capable of anchorage-independent cell growth in the soft agar assay like CB33-HMG-I (41) or CB33-myc cells. Bar, 0.2 mm. In B, the number of colonies formed by the all CB33-HMG cells and CB33-myc cells were similar. Transfections were performed in duplicate, and the results are taken from two separate experiments. {blacksquare}, mean from two different experiments; bars, SD. In C, the CB33-HMG-cells overexpress the appropriate HMG-I protein. Western analysis showing that the CB33-HMG-Y and CB33-HMG-C cells overexpress the HMG-Y and HMG-C protein, respectively, compared with control Rat 1a cells transfected with pSG5 vector alone. Lanes 1–4 were blotted with the HMG-I/Y antibody as well as a ß-actin antibody to control for sample loading; Lanes 5 and 6 were blotted with the HMG-C antibody. D, cell growth rates of the CB33 cell lines. This experiment was performed with duplicate plates and repeated twice. Bars, SD from a representative experiment. All CB33 cell lines grow at similar rates.

 
Rat 1a Cells with Ectopic Expression of HMG-I Proteins Are Tumorigenic in Nude Mice.
To verify the tumorigenic potential of the Rat 1a cells overexpressing HMG-Y or -C, we introduced these cells into athymic, nude mice and compared these results with those for mice injected with cells with increased HMG-I (41) or c-Myc protein. Tumors were visible in 3 of 5 mice injected with Rat 1a-HMG-Y cells and 6 of 10 mice injected with Rat1a-HMG-C cells (Table 1)Citation . In our previous studies, we found that 5 of 5 mice injected with Rat 1a-myc and 4 of 5 injected with Rat 1a-HMG-I cells formed tumors. No tumors formed in the mice injected with Rat 1a cells transfected with vector alone. The tumors were visible by day 30, and the average size of the tumors was 17.5 mm for mice injected with Rat 1a-HMG-Y cells and 11.3 mm for mice injected with Rat 1a-HMG-C cells by day 50 (Table 1)Citation . The pathology results show that the tumors are fibrosarcomas (Fig. 3Citation ) which is identical with results for tumors formed by Rat 1a-HMG-I (41) and Rat 1-myc (71) cells. In addition, several mice injected with Rat 1a-HMG-I or Rat 1a-HMG-C cells developed distant lung metastases (Table 1Citation ; Fig. 3DCitation ).


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  		Table 1 Tumor characteristics from nude mice injected with Rat 1a-HMG cellsa

 


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  		Fig. 3. Rat 1a-HMG-I cells form tumors in nude mice. A, Rat 1a-Y, Rat 1a-C, control Rat 1a-pSG5 cells, positive control Rat 1a-myc, and positive control Rat1a-HMG-I (41) cells were injected into nude mice. Only mice injected with Rat 1a cells overexpressing Myc, HMG-I (41) , -Y, or -C formed tumors. Pathological evaluation of the tumors showed that all tumors formed from Rat 1a-HMG or Rat 1a-myc cells were fibrosarcomas; x16 magnification of the large s.c. tumor in a mouse injected with the Rat 1a-HMG-Y cells (H&E). B, the tumor at x100. Note the occasional multinucleated giant cells (H&E). C, tumor from a mouse injected with Rat 1a-HMG-C cells at x250. Note the spindle-shaped cells (H&E). D, perivascular accumulation of metastatic tumor cells in the lung from a mouse injected with Rat 1a-HMG-C cells.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The HMG-I proteins are a diverse group of low molecular weight, nonhistone DNA binding proteins that function in organizing chromatin structure (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) . The HMG-I gene family encodes the HMG-I, -Y, and -C proteins, which were originally identified based on their association with chromatin structure (5, 6, 7, 8, 9, 10, 11) . HMG-I and -Y are products of alternatively spliced RNA (5, 6, 7) ; HMG-C is encoded by a related, but separate gene (10, 11) . The HMG-I proteins all contain 3 AT hook DNA-binding domains that enable these proteins to bind to AT-rich sequences in the minor groove of DNA (18 , 22, 23, 24, 25) . The AT hooks are of general interest because they have been identified in a variety of fusion proteins associated with human tumors (72, 73, 74) . For example, the AT hooks from HMG-C are present in chimeric proteins observed in lipomas and other benign mesenchymal tumors (42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62) . The chimeras result from rearrangements of the HMG-C gene at the 12q14–15 chromosomal breakpoints identified in many of these tumors (42 , 75) . Two distinct chimeras have been discovered in lipomas that contain HMG-C AT hooks fused to distinct, putative transcriptional regulatory domains (43) . In addition, regions homologous to HMG-I AT-hooks have been identified in the ALL-1 gene (also called MLL, HRX, and HTRX), which encodes a leukemia-specific chimeric protein (72, 73, 74) . In both the benign and malignant tumors, the AT hook regions are believed to bind to DNA, alter gene expression, and thereby contribute to the pathogenesis of the tumors (4 , 7 , 72) .

Increased expression of HMG-I/Y proteins correlates with rapidly proliferating, undifferentiated mammalian tissues as well as neoplastic transformation (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38) . HMG-I/Y genes and proteins are elevated in several malignant cell lines and human cancers (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38) . We have previously shown that HMG-I/Y is a c-Myc target gene (40 , 41) . HMG-I/Y proteins are elevated in Burkitt’s lymphoma cells (41) as well as other leukemia and lymphoma cell lines.5 HMG-I also displayed several oncogenic properties, including transformation of both Rat 1a and CB33 cells (40, 41) . Moreover, we showed that decreasing HMG-I/Y proteins inhibits transformation in Burkitt’s lymphoma (41) . Rat 1a cells with ectopic HMG-I expression were also tumorigenic in nude mice (41) . These findings suggest that HMG-I/Y proteins may be involved in the pathogenesis of malignancy.

Several recent studies also indicate an important role for HMG-I/Y proteins in transcriptional regulation (13, 14, 15, 16, 17, 18, 19, 20, 21) . HMG-I/Y proteins can increase transcription generally by relieving H1-mediated repression of transcription (19, 20, 21) . In addition, HMG-I/Y proteins have been shown to regulate gene expression more specifically (13, 14, 15, 16, 17) . For example, HMG-I/Y binds specifically to the IFN-ß promoter and recruits additional transcription factors to an enhancer (13, 14, 15, 16, 17) . HMG-I/Y also promotes cooperative binding of the involved transcription factors and results in bending of the DNA and formation of a higher order transcriptional complex, called an enhanceosome (13, 14, 15, 16, 17) . HMG-I/Y proteins have been implicated in the regulation of other genes, including E-selectin (76, 77) , nitric oxide synthase (78) , tumor necrosis factor ß (79) , interleukin 2 receptor {alpha} (80) , interleukin 4 (81) , human gp91-phox (82, 83) , epsilon-IgG (84) , and T-cell receptor {alpha} (85) . The identification of target genes involved in neoplastic transformation will enhance our understanding of the role of HMG-I/Y genes in malignancy.

In this paper, we show that increased expression of the HMG-I family members, HMG-Y and HMG-C, leads to the neoplastic transformation of Rat 1a and CB33 cells in a manner analogous to those of HMG-I (41) and Myc (66 , 69) . Moreover, Rat 1a cells with increased HMG-Y or-C proteins are tumorigenic like Rat 1a-HMG-I (41) or Rat 1a-myc (71) cells. Given that these gene products are elevated in several human malignancies, our findings suggest that HMG-I genes may represent a new family of human oncogenes important in the pathogenesis of several human malignancies.

The HMG-I proteins may participate in neoplastic transformation through a variety of possible mechanisms. First, HMG-I proteins could function by binding specifically to DNA upstream of genes involved in regulating cell growth. After binding to DNA, the HMG-I proteins could recruit additional transcription factors and bend DNA, forming a structure similar to the enhanceosome observed for the IFN-{alpha} promoter (13, 14, 15, 16, 17) . Alternatively, the HMG-I proteins could function more generally by binding to chromatin at several sites and altering chromatin structure, thereby increasing transcription less specifically (19, 20, 21) . Finally, HMG-I proteins may form a chimeric protein as reported for HMG-C that alters transcription of genes critical to cell growth and neoplastic transformation (42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62) . Although we have not yet elucidated the mechanisms involved, our data show that the HMG-I gene family has oncogenic properties and may represent a new class of oncogenes important in the pathogenesis of several human malignancies.


   ACKNOWLEDGMENTS
 
This work is dedicated to the memory of Dr. Daniel Nathans. L. M. S. R. initiated her study of HMG-I/Y in the Nathans’ laboratory and is indebted to Dr. Nathans for invaluable guidance, support, and inspiration. We also thank Dr. Chi V. Dang for advice and helpful discussions and Dr. Jonathon Simons for guidance and reagents used in the nude mice experiments.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by Grants 5K11CA59793 (L. M. S. R.), R29CA76130 (L. M. S. R.), Concern Foundation (L. M. S. R.), and 1T32CA604441 (L. J. W.). Back

2 Present address: University of Mississippi Medical Center/G.V. (SONNY) Montgomery Veterans Affairs Medical Center, Jackson, MS 39216. Back

3 Present address: DuPont Pharmaceutical Company, Stine-Haskell Research Center, Box 30, Elkton Road, Building S320, Newark, DE 19614-0300. Back

4 To whom requests for reprints should be addressed, at The Johns Hopkins University School of Medicine, Division of Pediatric Hematology, The Ross Research Bldg., Room 1125, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-955-6132; Fax: 410-955-8202; E-mail: lmsresar{at}welch.jhu.edu Back

5 L. M. S. Resar and L. J. Wood, unpublished data. Back

Received 2/ 4/00. Accepted 6/ 2/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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