This paper will be published with modifications in American Journal of Epidemiology 2003 April; 157(7): 571-82
5,10-Methylenetetrahydrofolate Reductase Polymorphisms
and Leukemia Risk
Print Version
Kim Robien, Cornelia M. Ulrich
Cancer Prevention Research Program [KR, CMU]
Fred Hutchinson Cancer Research Center, Seattle, WA 98109
Department of Epidemiology [CMU] and
Interdisciplinary Graduate Program in Nutritional Sciences [KR, CMU]
University of Washington, Seattle, WA 98115
Funding: Support for KR was provided by a training grant from the National Cancer Institute T32 CA80416.
Abbreviations used: ALL Acute lymphocytic leukemia; AML Acute myelogenous leukemia; CLL Chronic lymphocytic leukemia; CML Chronic myelogenous leukemia; cSHMT Cytosolic serine hydroxymethyltransferase; FAD Flavin adenine dinucleotide; MTHFR 5,10-methylenetetrahydrofolate reductase; MLL Myeloid/lymphoid or mixed lineage leukemia; MS Methionine synthase; RFLP Restriction fragment length polymorphism; SAM S-adenosylmethionine; SHMT Serine hydroxymethyltransferase; THF Tetrahydrofolate; TS Thymidylate synthase
Address correspondence to: Kim Robien, MS, RD, Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., MP-900, Seattle, WA 98109-1024 Phone: (206) 667-7946 Fax: (206) 667-7850
Email: krobien@fhcrc.org
Address for reprints: Cornelia Ulrich, PhD, Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., MP-900, Seattle, WA 98109-1024 Phone: (206) 667-7617 Fax: (206) 667-7850
Email: nulrich@fhcrc.org
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Abstract
Leukemias commonly arise as a result of DNA translocations, inversions, or deletions in genes regulating blood cell development or homeostasis. Folate deficiency has been associated with uracil misincorporation into DNA and DNA double strand breaks during uracil excision repair, thus increasing the risk of chromosomal aberrations. Methylenetetrahydrofolate reductase (MTHFR) directs 5,10-methylenetetrahydrofolate towards methionine synthesis at the expense of DNA synthesis. Two MTHFR polymorphisms, C677T and A1298C, have been associated with reduced enzyme activity and C677T with altered distribution of intracellular folate metabolites. Rapidly replicating cell types, such as hematopoietic cells, may be especially sensitive to changes in the availability of intracellular folate. Three case-control studies have evaluated the association between MTHFR polymorphisms and the risk of acute leukemia, and suggest that both adults and children with the variant forms of MTHFR have a decreased risk of lymphoid leukemias. However, no modification in risk has been observed for myeloid leukemias, suggesting that differences in folate requirements or susceptibility to chromosomal damage may exist between myeloid and lymphoid cells. Further investigation into the association between MTHFR polymorphisms and risk of leukemia is warranted, and should include larger sample sizes, other polymorphisms in folate metabolism, and address interactions with folate status.
Gene and Gene Product
The primary function of folate is as a carrier for single carbon fragments, including in the conversion of homocysteine to methionine, and in purine and pyrimidine synthesis. Figure 1 summarizes key enzymes of intracellular folate metabolism. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the irreversible reduction of 5,10-methylene tetrahydrofolate (THF) to 5-methylTHF, the primary form of serum folate. MTHFR has been described as being located at the branch point of directing folate metabolites towards remethylation of homocysteine and away from DNA and RNA biosynthesis (1)
. The gene for the MTHFR enzyme (EC 1.5.1.20) is found at the end of the short arm of chromosome 1 (1p36.3) (2)
. The cDNA sequence of this gene is approximately 2.2 kb, which includes 11 exons ranging in size from 103 bp to 432 bp (2, 3)
.
Gene Variants
There are two well described, commonly occurring polymorphisms in the MTHFR gene; C677T and A1298C. Other polymorphisms have been reported at bp 1059, bp 1289, bp 1317 and bp 1793 (4-6)
. These polymorphisms are less common than the C677T or A1298C polymorphisms and their functional relevance has not yet been investigated.
C677T polymorphism
The C677T polymorphism occurs in exon 4 and results in an alanine to valine substitution at codon 222. The polymorphism lies in the binding site for the MTHFR co-factor flavin adenine dinucleotide (FAD) (7)
. Individuals with the MTHFR C677T TT genotype have been shown to have 30% in vitro MTHFR enzyme activity as compared with the wildtype, whereas those with the heterozygous (CT) genotype have been found to have 60% of wildtype MTHFR enzyme activity (8)
. The 677T allele has been associated with elevated plasma homocysteine levels (9)
, a somewhat increased risk of cardiovascular disease (9-12)
and an increased risk of birth defects, especially neural tube defects (13-16)
. For a full review of the C677T polymorphism and its population frequencies, the reader is referred to the HuGE Review on MTHFR and congenital anomalies (15)
.
A1298C polymorphism
A second MTHFR polymorphism, A1298C in exon 7, results in a glutamate to alanine substitution at codon 429 (5, 13)
. This polymorphism lies in the S-adenosylmethionine-regulatory domain of the enzyme (17-19)
. The binding of S-adenosylmethionine (SAM) results in conformational changes within the MTHFR enzyme which inhibit the enzyme's activity (17)
. Lymphocytes from individuals with the 1298 CC genotype have been found to have approximately 60% of specific wildtype in vitro MTHFR activity (13)
, and individuals with both 677 CT and 1298 AC genotypes were found to have 50 - 60% of wildtype MTHFR activity (5, 13)
.
Population frequencies for the A1298C polymorphism are summarized in Table 1. The C allele frequency ranges from 0.17 – 0.19 among Asian populations to 0.27 – 0.36 in Western Europe. Little is known about A1298C allele frequencies among African or South American populations. The MTHFR C677T and A1298C sites are 2.1 kb apart and have been found to be in strong linkage disequilibrium (20, 21)
. Several groups have shown that the two polymorphisms very rarely exist on the same allele (5, 13, 20, 21)
, and the combined MTHFR 677 TT and 1298 CC genotypes are extremely uncommon in the general population. These findings suggest a founder effect in which each alteration evolved on a separate wildtype allele (20-22)
.
T1317C polymorphism
The polymorphism identified at bp 1317 is a thymine to cytosine substitution, but does not alter the amino acid sequence (5)
. The allele frequency for the 1317C variant was 0.05 among a group of 38 Canadian women, and 0.39 among 9 African-American women (5)
. Ray et al. reported a 1317C allele frequency of 0.03 among 129 Canadian women serving as controls in a case-control study of genetic risk factors for thrombophilia (24)
.
G1793A polymorphism
In a study of 507 individuals representing several ethnic backgrounds randomly selected from clinic populations in Texas and New York, Rady et al recently reported a guanine to adenine substitution at bp 1793, resulting in an arginine to glutamine substitution at codon 594 (6)
. They found an A allele frequency of 0.01 among Ashkenazi Jews (n = 155), 0.03 among African-Americans (n = 97), 0.07 among Caucasians (n = 159), and 0.06 among Hispanics (n = 95) (6)
. The functional relevance of this polymorphism has not yet been investigated.
Diseases
Leukemias, as a group, are cancers arising from hematopoietic cell lines. Genetic translocations, inversions or
deletions in hematopoietic cells disrupt the normal function of the genes at these locations, altering normal blood cell development (25)
. As a result, dysfunctional or non-differentiated leukemic cells accumulate in the bone marrow space and progressively replace normal hematopoietic cells. Signs and symptoms of leukemia include anemia, fatigue, bleeding and infections (26, 27)
. Leukemias can be either acute or chronic, and can arise from myeloid or lymphoid cell lines, or both, as in the case of myeloid/lymphoid or mixed lineage leukemia (MLL). The four major forms of leukemia are acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML) (28)
.
Acute leukemias are rare, accounting for only 2% of all cancers in the United States (29)
. Approximately 9000 individuals are diagnosed with AML, and 4000 individuals with ALL annually in the United States (30)
. ALL occurs more commonly among children and young adults, with a median age at diagnosis of 10 years, whereas the median age of onset for AML is 65 years (30)
. CLL is the most common form of leukemia in adults in Western countries, affecting approximately 10,000 individuals per year in the United States (31)
. CML affects approximately 4000 individuals per year in the United States with a median age of onset between ages 45 and 55 (32)
. Leukemia is the most common type of cancer among children, with ALL accounting for 75% of leukemia cases, AML 20%, and CML <5% (33)
.
While researchers have made significant strides in improving outcomes for individuals diagnosed with leukemia (34)
, very little is known of how the disease originates. Exposure to ionizing radiation (35-37)
, benzene (38, 39)
, pesticides (40)
, cigarette smoking (41-43)
and extremely low-frequency electromagnetic fields (40, 44)
have all been found to be associated with an increased risk of leukemia in adults.
A large body of epidemiologic research has evaluated the association between infection and the risk of pediatric leukemias, particularly ALL. Kinsley hypothesized that increased rates of leukemias are seen following periods of population mixing, which can introduce new infectious agents into a community of individuals who were previously unexposed or who may have susceptibility to the infectious agent (45)
. This theory has been corroborated by several studies reporting an increased risk of acute leukemias following periods of population mixing (46-53)
. Similarly, Greaves hypothesized that the development of leukemia is related to inadequate development of the infant immune response or a lack of exposure to infections in early childhood, resulting in an abnormal immune response when these children are later exposed to common infections (the “delayed infection” hypothesis) (54, 55)
. Although research using daycare attendance, sibship size and birth order as surrogates for early exposure to common infections has shown inconsistent results (56-59)
, studies directly assessing incidence of common infections report an inverse association between some, but not all, common infections, e.g. ear infections (56)
, and risk of leukemia (60)
. Down's syndrome has also been associated with an increased risk of pediatric leukemia (61, 62)
, primarily the acute myelogenous form (63)
.
Although single chromosomal aberrations have been identified as one of the causes of cellular dysfunction for many of the specific leukemia subtypes, it is likely that multiple genes and environmental factors play a role in an individual's susceptibility to these chromosomal aberrations (65)
. Dietary bioflavinoids, some of which are known topoisomerase II inhibitors, have been shown to cause site-specific DNA cleavage in the MLL gene breakpoint cluster region on chromosome 11q23 (66, 67)
. Maternal bioflavinoid intake during pregnancy has been associated with increased risk of infant leukemias (68)
. A study by Thompson et al among 83 children with ALL and 166 age- and sex- matched controls found an inverse association between maternal folate supplementation during pregnancy and risk of pediatric ALL, but did not evaluate MTHFR polymorphisms (69)
. Rodent studies of chemical or radiation induced leukemia have found that caloric restriction (70-72)
, curcumin (73)
, and the monoterpene geraniol (74)
may be protective against the development of leukemia
Associations
Biological Mechanisms
Folate is an essential nutrient for normal mammalian cell growth as a carrier of single carbon fragments. These reactions include purine and pyrimidine synthesis as well as the provision of methyl groups for DNA, RNA and protein methylation (75-77)
. Folate deficiency has been shown to result in uracil misincorporation during DNA replication (78, 79)
with subsequent increased double-strand breaks during uracil excision repair (80)
. Thus, an increased risk of leukemia-inducing translocations associated with low-folate status is conceivable.
Low-folate status has been associated with an increased risk of several types of cancer, especially colorectal cancer (75, 76)
(81-84)
. Yet, MTHFR 677 TT individuals with adequate folate levels have been found to have a decreased risk of colorectal cancer (85-87)
. Several authors (85, 86, 88)
have suggested that the explanation for this paradox is that in situations of decreased MTHFR activity, more of its substrate (5,10-methyleneTHF) is available for purine and pyrimidine synthesis, resulting in more stable DNA synthesis and decreased genetic mutations. This hypothesis was later supported by Bagley and Selhub who observed that erythrocytes from individuals with the wildtype MTHFR 677 CC genotype contained mostly 5-methylTHF, whereas individuals with the variant MTHFR 677 T genotype contained both formylated THF as well as 5-methylTHF (89)
. These findings demonstrate that decreased MTHFR activity results in an alteration of the normal intracellular distribution of folate substrates in favor of the precursors for purine and pyrimidine synthesis.
MTHFR polymorphisms and leukemia
Three case-control studies to date have addressed whether variant forms of the MTHFR gene alter the risk of leukemia (Table 2). In a study of adult acute leukemia cases (n = 71 ALL, 237 AML; age range: 16 – 70 years) and controls (n = 356) conducted in the United Kingdom, Skibola et al found that individuals with the MTHFR 677 TT, 1298 AC and CC genotypes have a decreased risk of ALL (90)
. The MTHFR 677 TT genotype was associated with a 4.3-fold decrease of ALL (odds ratio (OR) = 0.23; 95% confidence interval (CI): 0.06, 0.81; n = 5 cases, 14 controls) compared to the 677 CC genotype, whereas a 14-fold decrease in risk (n.s.) of ALL was observed among individuals with the MTHFR 1298 CC genotype (OR = 0.07; 95% CI: 0.00, 1.77; n = 1 case, 11 controls) compared to the 1298 AA genotype. No statistically significant differences were observed in MTHFR genotypes among cases with AML and controls, suggesting that MTHFR polymorphisms do not play a role in risk of AML. Odds ratios range from 0.73 – 1.00, and all confidence intervals include 1.0 (see Table 2).
Wiemels et al (19)
investigated whether the MTHFR C677T or A1298C polymorphisms altered the risk of pediatric AML, MLL or hyperdiploid leukemias. The study population included 253 cases (78 AML, 37 MLL, and 138 hyperdiploid leukemia) who were less than 15 years of age and participants in the United Kingdom Childhood Cancer Study and 200 unselected newborn controls from the Manchester, UK area. They found that the MTHFR 677 CT and TT genotypes (but not the 1298 AC and CC genotypes) were associated with a significantly decreased risk of leukemias with MLL rearrangements compared to wildtype (OR = 0.36; 95% CI: 0.15, 0.85; n = 11 cases, 111 controls). The variant MTHFR 1298 CC genotype (but not the 677 TT genotype) was associated with a significantly decreased risk of hyperdiploid leukemias (leukemias where the aberrant cells have accumulated additional chromosomes) (OR = 0.26; 95% CI: 0.07, 0.81; n = 5 cases, 23 controls). Neither of the two major MTHFR polymorphisms appeared to be associated with AML (see Table 2). A smaller study (71 cases, 71 controls; age range: 2 months – 15 years) of pediatric ALL from Brazil found that the presence of the MTHFR 677 T allele was associated with a 2.4-fold decreased risk of ALL (OR = 0.4; 95% CI: 0.2, 0.8; n = 34 cases, 49 controls), whereas the A1298C genotype did not significantly effect risk of ALL (91)
.
These studies suggest that the altered distribution of intracellular folate metabolites introduced by the variant forms of MTHFR may play a role in the risk of lymphoid forms of leukemia, but not myeloid leukemias. However, the sample sizes for disease subtypes in these studies were small, and the findings need to be confirmed in larger populations. Although it is not entirely clear why this disparity between lymphoid and myeloid forms of the disease has been observed, it suggests that differences in folate requirements or susceptibility to chromosomal damage may exist between myeloid and lymphoid cells. One group has suggested that lymphoid cells may have a higher folate requirement than myeloid cells, and therefore, may be more susceptible to DNA damage as a result of folate deficiency than myeloid cells (90)
. None of the studies to date have assessed dietary folate intake to evaluate whether overall folate status may have modified the relationship between MTHFR genotype and risk of leukemia.
Interactions
Gene-environment interactions
Conflicting results among studies investigating MTHFR polymorphisms and risk of various forms of cancer may be due to the lack of information on dietary folate intake or other measures of overall folate status. With respect to colorectal carcinogenesis, studies that have investigated both MTHFR polymorphisms and dietary folate intake or plasma folate levels have found a trend towards homozygous variants of MTHFR genotypes adversely affecting adenoma or cancer risk only in individuals with low dietary folate intake or plasma folate levels (86, 88, 92)
. Individuals with the MTHFR 677 TT genotype with normal plasma folate concentrations have been found to be at decreased risk of colorectal cancer relative to those with the CC genotype (85, 86)
. These findings demonstrate that the risk associated with the MTHFR 677 TT genotype varies depending on folate status. There have been no reports to date describing the effects of dietary folate intake on the association between the MTHFR 1298 polymorphism and risk of cancer.
Dietary intake of several other nutrients could also affect the distribution of intracellular folate metabolites. Vitamins B6 and B12 are cofactors for the enzymes serine hydroxymethyltransferase (SHMT) and methionine synthase (MS) respectively. Dietary adequacy of these nutrients may affect substrate availability for DNA synthesis and MTHFR activity. Dietary intake of protein-rich foods (especially meats, fish and cheeses) will influence the supply of the amino acid methionine. Chronic, excessive use of alcohol may take the place of more nutrient-dense foods in the diet, leading to deficiencies in folate and other B vitamins. Alcohol intake may also affect folate absorption, metabolism and renal excretion (93)
. While these gene-nutrient interactions have not been studied with respect to the risk of leukemia, studies have found that individuals with the MTHFR 677 TT genotype and diets low in vitamins B6, B12, methionine and folate, and high in alcohol are at increased risk of developing colorectal tumors (85, 87, 88, 92, 94)
.
The amino acid affected by the MTHFR C677T polymorphism affects the binding site for flavin adenine dinucleotide (FAD), a cofactor for the MTHFR enzyme (7)
. The thermolabile form of the MTHFR enzyme (677 TT genotype) has been shown to dissociate with the FAD cofactor more readily than the wildtype enzyme resulting in decreased enzyme activity (7)
. In situations where there is abundant intracellular folate, the folate molecule may be able to hold the variant MTHFR protein in the appropriate and functional three-dimensional structure (7, 95)
.
As FAD is a form of the B vitamin riboflavin, riboflavin status has also been suggested as playing a role in optimal MTHFR activity. Two studies to date have investigated the relationship between riboflavin and MTHFR genotypes using total plasma homocysteine levels as the outcome variable of interest. Husted el al found plasma riboflavin levels to be an independent determinant of plasma homocysteine levels in a study of 423 healthy blood donors between the ages of 19 and 69 in Norway (96)
. However, in a subsequent study, Jacques et al reported that plasma riboflavin status only affected total plasma homocysteine levels among individuals with both the MTHFR 677 TT genotype and low plasma folate levels in a subset of 450 participants in the Framingham Offspring Study cohort (97)
. Neither study evaluated the effects of dietary riboflavin and folate on MTHFR activity or total plasma homocysteine levels.
Gene-gene interactions
Other proteins involved in folate-mediated one-carbon metabolism, such as MS, thymidylate synthase (TS), SHMT, dihydrofolate reductase and the reduced folate carrier protein, have been well characterized. Each plays a role in the regulation of the various forms of intracellular folate, and variant forms of these enzymes may contribute to the risk of DNA instability and cancer. As shown in Figure 1, folate metabolism is complex and involves several regulatory mechanisms. Thus, genetic variation affecting protein function at any step may alter the balance of metabolites, and gene-gene interactions between polymorphisms in folate-metabolizing enzymes are likely. A detailed review of folate metabolism and its genetic variability is beyond the scope of this review, and the reader is referred elsewhere (98)
.
In a further analysis of their case-control study of adult patients with ALL, Skibola and colleagues investigated the association between polymorphisms in the MS, cytosolic SHMT (cSHMT) and TS genes and risk of adult ALL (65)
. Univariate analysis showed that individuals who were either homozygous or heterozygous for the variant forms of the cSHMT or TS genes had a decreased risk of ALL, however no significant associations were observed for the MS polymorphism. When interactions between the cSHMT polymorphism and TS or MS genes were evaluated, the variant cSHMT allele was associated with a greater than 13-fold decreased risk of ALL among individuals with a homozygous triple-repeat in the promoter region of the TS gene (OR=0.07, 95% CI: 0.0067, 0.77), and a 5.6-fold decreased risk of ALL among individuals who were heterozygous for the variant form of the MS gene (OR=0.18, 95% CI: 0.05, 0.63). Although these investigations of gene-gene interaction were hampered by small sample sizes, they illustrate the potential for interaction between multiple genetic variants in folate metabolism.
Laboratory Tests
MTHFR genotype determinations can be assessed by direct sequencing or restriction fragment length polymorphism (RFLP) assays as discussed in the previous HuGE Review on MTHFR gene variants and congenital abnormalities (15)
. All of the studies reviewed in this article reported using PCR/RFLP analysis for genotyping. More recently, multiplexed genotyping for simultaneous assessment of multiple polymorphism sites including MTFHR has been reported (99-101)
, although no data on the specificity, sensitivity, and predictive value of these testing methods are available.
Population Testing
There is still too little known about the disease risk associated with genetic polymorphisms in folate-metabolizing enzymes to advocate population testing at the current time. As previously mentioned, adequate dietary folate intake may be sufficient to overcome any potential detrimental effects of variant MTHFR transcripts, and public health measures to encourage increased dietary folate consumption appear to be the most beneficial approach at this time. Larger studies of leukemia, that take folate status into account are needed.
Gaps and Research Priorities
Research into the role of MTHFR polymorphisms in hematologic malignancies is still in the early stages. We suggest these additional research priorities:
Larger sample sizes needed. Leukemias are relatively rare malignancies, accounting for only 2% of all new cancer cases predicted to be reported in the United States in 2002 (29)
. As a result, studies to date have been relatively small. Small studies often lack adequate representation in certain genotype groups, can not adequately address gene-gene or gene-environment interactions, and can also be subject to publication bias. Large, well-designed studies are needed, and will likely require multicenter or multinational collaborations.
Gene-environment interactions must be addressed. There is sufficient evidence from studies investigating the role of MTHFR polymorphisms in other diseases indicating that intracellular folate levels may modify the effects of the MTHFR C677T and A1298C polymorphisms. Studies that do not assess folate status (e.g. by measuring dietary intakes or using biomarkers) may not be able to discern the true associations between MTHFR polymorphisms and leukemia risk. An assessment of folate status should be included in studies investigating genetic polymorphisms in folate-metabolizing enzymes.
Consider genetic variability in several proteins in folate metabolism concurrently. Folate metabolism involves several key enzymes that all contribute to the intracellular folate flux. It is likely that if folate status truly influences risk of leukemia, a better understanding of genetic variability within multiple proteins in the pathway will help to more precisely assess an individual's risk level.
Further exploration into the structure and properties of the various polymorphic forms of human MTHFR is needed. No one has been able to express sufficient quantities of the human MTHFR protein to allow for structural determinations to date. Therefore our understanding of MTHFR structure and function has been extrapolated from other organisms, such as E. coli (7)
; an organism with 34% sequence homology with the human [UniGene Cluster HS.214142]. Structure information may provide a molecular basis for the observation of decreased activity of the variant forms of MTHFR, demonstrate the degree to which each polymorphism affects the function of the molecule, and elucidate the role that environmental factors such as intracellular levels of folate and riboflavin play in regulating MTHFR activity.
Investigate gene-environment interactions in utero. Interactions between maternal and fetal MTHFR polymorphisms, maternal folate intake during pregnancy, and their effects on the subsequent risk of pediatric leukemia also warrant further exploration. It is known that the initiation of infant leukemias can occur in utero based on findings of leukemic translocations in neonatal blood spots (102-104)
, the presence of leukemia in newborns, and from studies of monozygotic twins with identical leukemic rearrangements (105-108)
. However, a recent report by Mori et al found that the presence of the common leukemia fusion genes TEL-AML1 and AML1-ETO among healthy newborns is 100-fold greater than the risk of leukemia, indicating that additional genetic and/or environmental exposures are required for the development of leukemia (104)
.
Concluding Remarks
While studies investigating the association between MTHFR genetic polymorphisms and the risk of leukemia to date have lacked statistical power, their results are intriguing and quite consistent. Future studies should have adequate statistical power for investigating combinations of the two MTHFR polymorphisms and those of other folate-metabolizing enzymes, as well as alterations in risk depending on folate status.
Figure 1
Tables 1 & 2
Print file of this review
Internet Sites
Online Mendelian Inheritance in Man (National Center for Biotechnology Information)
5,10-Methylenetetrahydrofolate reductase; MTHFR
ENZYME (Swiss Institute of Bioinformatics)
NiceZyme View of ENZYME: EC 1.5.1.20 (Methylenetetrahydrofolate reductase)
SWISS-PROT (Swiss Institute of Bioinformatics) NiceProt View of SWISS-PROT: P42898 (MTHR_Human)
SNP500Cancer Database (National Cancer Institute)
Cancer Genome Anatomy Project (National Cancer Institute)
Environmental Genome Project (National Institute of Environmental Health Sciences)
Leukemia Home Page (National Cancer Institute)
The Leukemia and Lymphoma Society
