MHC and Leukemia
M. Tevfik Dorak, MD, PhD
The first attempt to correlate a polymorphic system with disease susceptibility was made following the discovery of red blood cell groups. On the assumption that such polymorphisms must be maintained by selection, a search for associations between blood groups and specific diseases was initiated. The first such association was found between blood group A and stomach cancer in 1953 1. With the discovery of the H-2 and HLA systems and typing methods for them, it was inevitable that the MHC would be the subject of extensive disease association studies.
Mice: Initial studies on susceptibility to mouse leukemia were done without much knowledge of the H-2 complex. Gross showed that when cell-free filtrates from AKR or C58 mice (inbred strains with a very high incidence of spontaneous leukemia) were injected to newborn mice of C3H/Bi or C57BR/cd strains (with low natural leukemia incidence), leukemia developed, whereas, the adult mice were resistant 2;3. Interestingly, these four strains (AKR, C58, C57BR, C3H) all had the same MHC haplotype, H-2k 4;5. In 1964, Lilly et al, convincingly showed the role of the H-2k haplotype on the development of leukemia by inoculating leukemic extracts into mice from segregating generations with different H-2 types 6. The H-2k haplotype caused increased susceptibility to both 'virus-induced' and 'spontaneous' leukemia but only in homozygous form. The following studies of Lilly and others continued to show that spontaneous leukemia development was influenced by H-2k as much as virus-induced leukemia 7;8. In Lilly's studies, the H-2k homozygotes had a high incidence of spontaneous leukemia at about the same age (7-11 months) as the peak incidence period in AKR mice, whereas, their heterozygous (H-2b/k) littermates showed a somewhat lower leukemia incidence occurring gradually in their life span, generally later than 11 months 7. Other mouse studies revealed that the MHC also influences several other cancers spontaneously occurring 9, virally-induced 10 or chemically-induced 11.
The influence of homozygosity for the H-2k haplotype has been repeatedly confirmed in many other studies 8;12-16, and one of the several leukemia susceptibility loci has been mapped to the MHC class II region 15-18. Heterozygosity for the H-2k haplotype has no effect on leukemogenesis in mice. Reviews of earlier studies concluded that the studies where the H-2b haplotype had been included, it seemed to favor resistance to virally-induced oncogenesis including leukemogenesis 19-21. The resistance is not absolute and shows itself as later onset rather than no occurrence. Similar to Lilly’s studies on mouse leukemia, a more recent lymphoma model shows this point clearly. In a virally-induced lymphoma model in mice, 64% of animals of susceptible strains (H-2I-Ak/k) developed T-cell lymphoma with a mean latency period of 37 weeks. In resistant strains (H-2b/b or H-2b/k), only 14% of the mice developed lymphomas with a longer latency of 57 weeks. The mouse studies concluded that the contribution of the MHC to the development of leukemia is secondary and mainly on the age at onset in a polygenic and multifactorial context 12;22;23. It is also well-established that the interaction of the MHC is not on transformation of a neoplastic clone but occurs during the preleukemic phase 10;22. Although various mechanisms have been postulated for this effect, at present, there is only evidence to support an immune response related one 13-18. Similar conclusions have been drawn also from other animal models 24-26. Besides the H-2 type, female gender has been identified as another factor in determination of an effective immune response for murine leukemia viruses 14.
Rat: Susceptibility to the growth of transplantable gliosarcoma in genetically inbred rats has a correlation with the MHC type 27. Curiously, however, this effect is a dominant one. The presence of antibodies to histocompatibility antigens which were those of the strain in which the tumor originated predicts tumor regression which suggests an immune mechanism in operation. More recent studies showed striking correlations between chemical tumor induction and the growth and reproduction complex (grc) of the rat MHC 28-32. The grc was discovered in 1979 by Gill and Kunz 33 as an MHC-linked gene complex affecting growth and development. It is homologous to the Q/TL region of the mouse, and homozygosity for a 70 kb deletion in this region are associated with embryonic death, developmental defects, and decreased resistance to cancer 34;35. The mechanism of increased susceptibility to cancer is unknown. If a similar region exists in humans, it would be at the telomeric end of the class I region 36;37.
Cattle: Bovine leukemia virus (BLV), a retrovirus, is associated with enzootic bovine leukosis, which is the most common neoplastic disease of cattle. Its infection appears as persistent lymphocytosis in one-third of cases and then some cases (1-5% of the total infected) proceed to lymphosarcoma 38. The first genetic factor in susceptibility to BLV infection was identified to be the bovine MHC (BoLA). In an early study, particular antigens, namely the class I antigens W6 and Eu28R, were found to be more frequent in cattle with persistent lymphocytosis 39. Later molecular studies mapped the susceptibility and resistance to BLV-induced persistent lymphocytosis to the (non-expressed) BoLA-DRB2 and -DRB3 loci in the class II region and showed that the previous class I associations were due to linkage disequilibrium 38;40;41. Resistance conferred by (DQA*3A-DQB*3A)-DRB2*2A-DRB3.2*11, *23 or *28 is dominant and almost absolute, whereas, susceptibility is associated with homozygosity for the haplotypes DRB2*1C-DRB3.2*16, *22, or *24; or (BoLA-A14-DQA*12-DQB*12)-DRB2*3A-DRB3.2*8 and not absolute. The map position of susceptibility or resistance has been further refined and located at the amino acid positions 70 and 71 in the second exon of BoLA-DRB3.2 molecule 24. All resistance alleles have the amino acids Glu70 (E) and Arg71 (R) in these positions, and the susceptibility alleles do not have either of them. Since these amino acids are involved in peptide binding, it has been concluded that the cellular immune response is important in preventing in vivo spread of BLV infection. Indeed, DRB3 or a closely linked gene appear to control the number of BLV-infected peripheral B cells in vivo 38. The animals with the susceptibility genotypes tend to have a larger number of BLV-infected B lymphocytes. A four amino acid homology between susceptibility associated DRB3 alleles (residues 75 to 78) and BLV pol protein led to the speculation that molecular mimicry could be involved in susceptibility 24.
Chicken: The MHC of the chicken is traditionally called the B complex and completely sequenced 42. The class I region (B-F) has been extensively studied because of its association with susceptibility to Marek's disease (MD) which is the most prominent naturally occurring disease of chickens. MD is a herpes virus-induced lymphoproliferative disease. Genetic resistance to Marek's disease was mapped to the B complex after a lucky recombination event 43. That first observation showed that the haplotype B21 was resistance and B19 was susceptibility markers. Following studies mostly agreed with the finding that B21 was the resistance haplotype 44 and also showed that the B2 haplotype had the same effect 45;46. Viremia levels at day 5 and 6 postinfection were found to be lower in chickens bearing the B2 haplotype compared to those with the susceptibility haplotypes 45. The most significant influence of the MHC on Rous sarcomas is on their regression or progression 47-50. The interesting feature of the B-F association with this virus-induced malignancy is the dominant nature of the resistance and the interaction of the MHC genotypes with gender, males being the worst affected one in susceptibility 51 and mortality 52. With the availability of the complete sequence of the chicken B complex, an interesting possibility arouse that the presence of the putative NK cell receptor gene(s) may be the reason for the MHC-linked susceptibility to Marek's disease 42.
Similarly, Rous Sarcoma Virus (RSV) -induced malignancy is also associated with certain B complex genotypes 49. The B2 haplotype is again the resistance haplotype and B5 is the susceptibility marker 50;53;54 although other associations were also reported 55;56. The metastatic behavior of tumors also shows a correlation with the MHC type with a gender effect. Metastasis is less frequent in chickens with the B2 haplotype and this genotype interacts with the sex of the chicken, again maleness being the unfavorable of the two 53. The consistent pattern continues for RSV-induced tumors that susceptibility genotypes are homozygous 57 and resistance appears to be dominant 56. The mechanism of the MHC association with RSV-induced tumor development and its clinical course is almost certainly immunological 58;59, and a possibility of molecular mimicry between a B5 antigen and the virus has been suggested to be the reason for susceptibility 25;60.
Avian Leukosis Virus (ALV) causes erythroblastosis in chickens and this malignancy is also associated with the B complex 50;61. It is important that the same B2 haplotype is the resistance marker against this virus, although another study found the same effect associated with B21 61. This means that all three virus-induced malignancies of chickens, Marek's disease, Rous sarcoma and erythroblastosis share the same MHC-associated susceptibility (B5, B15) and resistance genotypes (B2, B21) 50;54;59. This unusual situation is similar to the H-2b-associated protection from malignancies in mice and strongly suggests the involvement of an immune response component in this phenomenon.
Rabbits: Regression or malignant conversion to squamous cancer of skin warts induced by papillomavirus show strong correlations with MHC class II alleles by RFLP analysis in rabbits 26. This finding suggests an immune system mediated influence of the MHC on virus-induced cancer in another animal.
The consistent finding in animal studies that resistance is dominant and susceptibility is recessive, is in agreement with expectations based on the classical model for immune response gene control 62. Another unambiguously established conclusion is that all MHC associations, with the notable exception of the grc effect in rats, seem to result from immune responsiveness to an oncogenic virus or tumor antigens. The immune non-responsiveness may be the result of molecular mimicry in the BLV infection in cattle and Rous sarcoma in chickens. Although not noted in all studies, a gender effect suggesting a stronger effect of the MHC in susceptibility to virus-induced neoplasms in males appears to be consistent.
By the beginning of the 1990s, studies on the role of the HLA system in human leukemia susceptibility reached a stage where a large amount of data was generated and many questions were raised but few firm answers were available. The field of HLA-disease associations, in general, has been characterized by a combination of a large number of reports, unknown mechanisms and unconsidered implications. Unfortunately, the literature is now saturated with unconfirmed association reports most of which were spurious associations as would be expected from the analysis of such a polymorphic system. As early as 1972, Walter Bodmer had pointed out that "the search for associations of red blood cell groups with diseases has been a most frustrating one producing inconsistencies and statistical pitfalls. The problems of these studies should be a warning to investigators looking for associations between the HL-A polymorphism and diseases" 63. This warning did not have a great effect. Today, similar warnings are issued for pharmacogenetic studies quoting the current state of HLA and disease association studies 64. There is still no standardization in the methodology of HLA and disease association studies and statistical analysis of such data largely depends on arbitrary choices of methods. The statistical aspects of HLA and disease associations are discussed elsewhere (HLA and Disease Association & Statistics Analysis).
HLA association studies: The first HLA study on human leukemia found an increased frequency of HLA-A2 in ALL in 1967 65. In the same year, another HLA disease association was reported also with a hemopoietic malignancy; this time between the HLA-B broad specificity 4c and Hodgkin's disease 66. No doubt that the initial studies concentrated on leukemias because of the finding of the first MHC association in mouse leukemia in 1964 6. A second study in ALL extended the first HLA-A2 association to HLA-A2B12 haplotypical association in 1970 67. Although not confirmed in all studies 68, the HLA-A2 association is one of the few leukemia associations noted in more than one study and in fact, a significant association in pooled data 69.
A number of other studies have investigated HLA associations in childhood and adult leukemias some of which included the analysis of HLA-DR/DQ antigens or genes 70-89. Most of these studies examined large number of patients and controls and employed the best available typing techniques of the time. It was, however, hardly the case that two studies ever showed the same result. The largest HLA association study in leukemia was carried out on the International Bone Marrow Transplant Registry data 77;78. These studies analyzed a total of 1,834 patients with ALL, AML, and CML treated between 1969 and 1985. These studies showed that HLA-Cw3 and -Cw4 are both susceptibility markers for all of the three major leukemias. It is not easy to explain that two different alleles of the same locus are associated with increased susceptibility to the same disease. To complicate the issue further, a following single-centre study showed an association also with HLA-Cw7 in ALL 79. Such a situation may arise if these HLA-C alleles share a broad specificity or a common epitope such as those recognized by NK cells. In the molecular era, an RFLP study suggested that HLA-Cw4 association with CML might be due to its linkage disequilibrium with BF*F which is the main association 85. A recent PCR study in childhood ALL failed to show any association with HLA-C alleles, and more specifically with the two sequence variants (NK1 and NK2) which are ligands for NK cell receptors 89. It appears that the reported HLA-C associations may be the consequence of expression differences between leukemic and healthy cells. Confirmed and consistent HLA associations found in leukemias are shown in Table 1.
While HLA class I studies showed associations with HLA-A2(B12) and several HLA-C alleles, MHC class III loci was the subject of only one study in childhood ALL 90. A serological North American study of Factor B phenotypes revealed a significant association with BF*F (RR = 3.62; p<0.0001). This finding has not been confirmed in another study in childhood ALL. The only other MHC class III study in leukemia was published by Dorak et al. 85. This RFLP study in CML showed a BF*Fb association which was restricted to the patients below the median age (RR=3.1; p<0.01). This allele also had a significantly higher frequency in the male patients below median age compared to the older patients (p=0.014). This study was the first to suggest that MHC associations in leukemia may differ in genders as in some animal studies showed 14;51-53.
The first HLA-DR studies in childhood ALL showed an increase for HLA-DR7 70-72. In one study, adult ALL showed a weak association with HLA-DR4 80 and in another CLL was associated with HLA-DR53 81. The strongest association in leukemia reported to date has been presented by Seremetis et al 82. They used a monoclonal antibody specific for the HVR3 epitope of HLA-DR53 and found a RR of 7.88 (P<0.000005) for AML. Also, in the only molecular studies examined the HLA-DRB loci, directly or indirectly, in ALL, CML and CLL, the homozygous genotype for HLA-DRB4*01 (-DR53) had an increased frequency in patients 85-87;91. In childhood ALL, this effect was observed only in male patients 86;91. It thus appears that in the HLA-DR region, the HLA-DRB4 locus is the susceptibility marker for all major leukemias (AML, ALL, CML, CLL) examined so far. Despite being a consistent association in the recent studies, this association has not been noted before as strongly as it is 70-72;80;81 or has been missed completely 73-76;78;79;83;84;88;92. The explanation may be that none of the previous studies examined homozygosity, supertypes and gender effect simultaneously.
A possibility has been raised that the then putative HFE gene could be a susceptibility gene for childhood leukemias 93. Dorak et al. noted the similarities between the HLA-A3-related susceptibility genotypes for hereditary haemochromatosis (HH) and childhood ALL (as well as CML). Considering some epidemiological links between HH and cancer, the genetic mapping of an HLA class I-like gene (TCA) associated with leukemias to the area where HFE was thought to map, the possibility of a physical interaction between the TCA protein and the transferrin receptor (TfR), they proposed that HFE would be a HLA class I-like gene, map to the area telomeric to HLA-A, and be relevant in susceptibility to childhood ALL. Since the HFE gene is now found about 5 cM away from the HLA-A gene 94, it has been possible to test this hypothesis. Indeed, it has been shown in two different populations that the C282Y mutation of the HFE gene is a susceptibility marker for childhood ALL but only in males 95.
Other studies regarding the HLA system: In addition to HLA associations in leukemias, patients with leukemia have an increase in the frequency of HLA-identical siblings 85;92;96-98, in overall homozygosity for HLA antigens 98;99, and in HLA identity with their mothers where parents share one DR antigen 98. Parental HLA sharing is also increased in leukemic families which is most significant for the HLA-DR antigens 92;98-102.
Chan et al found that 35% of unaffected siblings have the same HLA genotypes as the leukemic patient although 25% was the expected frequency 92. Dorak et al reported the same in CML but only in the patients with a young-onset 85. Patients below the median age (number of siblings = 97) had a 37.7% HLA-identical sibling frequency whereas it was 24.7% for older patients (number of siblings = 81). In another study, HLA genotypes were established in patients with AML and in their first-degree relatives 98. Besides the excess of identical antigens (especially HLA-DR) between parents, there was a genetic distortion favoring HLA homozygosity in the affected offspring. The distribution of HLA-DR antigens shared by the parents markedly favored phenotypical HLA-DR identity of patients with their mothers as compared to fathers. This can be possible only if the paternally shared (and disease-associated) haplotype has a high transmission ratio relative to its homologue haplotype. This suggestion was used by Dorak & Burnett as one of the elements in their hypothesis that a t-like HLA haplotype may be relevant in susceptibility to leukemia 103. The mouse t haplotypes contain recessive deleterious genes (or embryonic lethals) most of which are within the MHC 104;105, and high transmission rates due to several transmission ratio distorter (tcd) genes the strongest of which (tcd-2) is again within the MHC or very close to it 106-108.
Von Fliedner et al reported the behavior of HLA-DR antigens in the families of 55 children with ALL 99. Their findings were: (i) increased identity at HLA-B and -DR loci between parents; (ii) twice as many as expected homozygotes among the patients where parents shared HLA antigens, and (iii) significantly more heterozygotes for the shared antigens among healthy siblings. Like the above-mentioned ones, these results point out high transmission ratios for HLA-associated HLA haplotypes too. The same researchers also reported an HLA-DR7 association in childhood ALL with an increased homozygosity rate for it 71. Neither in their studies nor in any other study, transmission ratios of particular antigens were studied in leukemia.
The first study examined the transmission ratios of HLA haplotypes was by Albert et al 109. That study included 535 families and concluded that although unexpected, the HLA-A2B12 haplotype had a high transmission ratio (60.0%). A more recent but much smaller study provided some evidence that this initial finding may hold in a different population 110;111. Komlos et al reported that the HLA-A2Bw4 haplotype had a higher transmission ratio when inherited form fathers. In another small study, the haplotype HLA-B44DR4 showed a high transmission ratio (65.8%) in healthy families 85. It appears that the commonest HLA-DR53 group haplotype or its parts may indeed show segregation distortion in a t-like manner. This issue is far from being concluded but it is certainly feasible to pursue it further.
The overall interpretation of these observations is that HLA associated leukemia susceptibility is a recessive trait and most probably HLA-DR-related. The recessive nature of MHC and leukemia / cancer associations has also been shown in animal studies in mice, chickens and cattle as outlined above. Another interpretation is that (paternal) transmission ratio for the leukemia-associated HLA haplotypes is increased which results in the violation of Mendelian expectations in HLA-identical sibling frequency. This would also cause the increased maternal identity where parents share an HLA-DR antigen 85;103. There is some suggestion that the haplotypes of the main leukemia susceptibility allele, HLA-DR53, may show segregation distortion which would result in increased homozygosity in patients.
Finally, an important but not well-recognized study investigated the correlation between HLA class I antigen frequencies and cancer incidences (measured as mortality rates) in 26 different populations 112. The most striking correlation was found between HLA-B8 antigen frequencies and intestinal cancer mortality rates in most of the populations examined. It is important to note that Scotland has the highest correlation while England and Wales also show a very high correlation. This study suggests that in general the HLA system may be relevant in cancer susceptibility and this varies among different populations. Unfortunately, this study has not been repeated for HLA class II antigens.
HLA expression in malignancies: Although genetically determined polymorphism in the MHC genes is relevant in determination of susceptibility to leukemia and other cancers, there is another role played by the MHC molecules in cancer. In cancers, MHC expression may be altered. This may be an increase, aberrant expression, down-regulation or abrogation. The functional significance of these changes varies 113. Cancer cells that present tumor antigens to the immune effector cells may elicit antitumor responses. In the absence of a co-stimulatory signal, engagement of the TCR by MHC class II and peptide complex may lead to selective anergy of tumor-specific clones. Alternatively, expression of class II antigens may promote tumor growth as it may recruit T cells that deliver stimulatory cytokines. Such changes usually occur after the transformation and may be influential in the determination of the fate of cancer cells. The correlation of expression of HLA-DR and -DQ molecules with favorable prognosis in breast cancer 114-116 and cervical cancer 117 has been reported.
Changes in HLA class I expression patterns have also been noted in a variety of tumors 118;119. HLA class I alterations may occur at a particular step between the development of an in situ lesion and an invasive carcinoma 118. The loss of class I expression results in the loss of immunosurveillance leading to invasion and/or metastasis in colon cancer 120, cervical cancer 117;121;122, breast cancer 114;123 and malignant melanoma 124. It is a consistent finding that while HLA class II expression may generally be a favorable sign, loss of HLA class I expression is a poor prognostic sign. An interesting feature of down-regulation of HLA expression in tumors is its association with oncogene activation 125;126.
Table 1. HLA system in Leukemia
1. Allelic associations
2. Increased parental HLA-DR sharing; increased maternal HLA-DR identity in such families
3. Increased homozygosity for HLA-DR antigens
4. Increased HLA-identical sibling frequency
5. Aberrant expression or loss of expression
6. Increased miscarriage frequency in the mothers of leukemia patients (relationship to the HLA system has not been investigated)
(see also HLA-DR53 fact file)
1. Aird I, Bentall HH, Roberts JAF. A relationship between cancer of stomach and the ABO blood groups. British Medical Journal 1953; 1: 799-801.
2. Gross L. Susceptibility to suckling-infant, and resistance of adult, mice of the C3H and of the C57 lines to inoculation with AK leukemia. Cancer 1950; 1073-1087.
3. Gross L. Viral (egg-borne) etiology of mouse leukemia. Cancer 1956; 9: 778-791.
4. Gorer PA. Some recent work on tumor immunity. Advances in Cancer Research 1956; 4 : 149-186.
5. Gross L. Viral etiology of mouse leukemia. Advances in Cancer Research 1961; 6: 149-180.
6. Lilly F, Boyse EA, Old LJ. Genetic basis of susceptibility to viral leukemogenesis. Lancet 1964; ii: 1207-1209.
7. Lilly F. The inheritance of susceptibility to the Gross leukemia virus in mice. Genetics 1966; 53: 529-539.
8. Boyse EA, Old LJ, Stockert E. The relation of linkage group IX to leukemogenesis in the mouse. In: Emmelot P, Bentvelzen P, eds. RNA Viruses and Host Genome in Oncogenesis, Amsterdam: North Holland Publishers Co., 1972: 171-185.
9. Faraldo MJ, Dux A, Muhlbock O, Hart G. Histocompatibility genes (the H-2 complex) and susceptibility to spontaneous lung tumors in mice. Immunogenetics 1979; 9: 383-404.
10. Chesebro B. Influence of the major histocompatibility complex (H-2) on oncornavirus-induced neoplasia in mice. In: Kaiser HE, ed. Neoplasms - comparative pathology of growth in animals, plants, and man, Baltimore: Williams and Wilkins, 1981: 475-482.
11. Oomen LC, Van der Valk MA, Hart AA, Demant P, Emmelot P. Influence of mouse major histocompatibility complex (H-2) on N- ethyl-N-nitrosourea-induced tumor formation in various organs. Cancer Research 1988; 48: 6634-6641.
12. Lilly F, Pincus T. Genetic control of murine viral leukemogenesis. Advances in Cancer Research 1973; 17: 231-277.
13. Meruelo D, McDevitt HO. Recent studies on the role of the immune response in resistance to virus-induced leukemias and lymphomas [Review]. Seminars in Hematology 1978; 15: 399-419.
14. Nowinski RC, Brown M, Doyle T, Prentice RL. Genetic and viral factors influencing the development of spontaneous leukemia in AKR mice. Virology 1979; 96: 186-204.
15. Vlug A, Schoenmakers HJ, Melief CJ. Genes of the H-2 complex regulate the antibody response to murine leukemia virus. Journal of Immunology 1981; 126: 2355-2360.
16. Vasmel WL, Zijlstra M, Radaszkiewicz T, Leupers CJ, de Goede RE, Melief CJ. Major histocompatibility complex class II-regulated immunity to murine leukemia virus protects against early T- but not late B- cell lymphomas. Journal of Virology 1988; 62: 3156-3166.
17. Lonai P, Haran Ghera N. Resistance genes to murine leukemia in the I immune response gene region of the H-2 complex. Journal of Experimental Medicine 1977; 146: 1164-1168.
18. Miyazawa M, Nishio J, Chesebro B. Genetic control of T cell responsiveness to the Friend murine leukemia virus envelope antigen. Identification of class II loci of the H-2 as immune response genes. Journal of Experimental Medicine 1988; 168: 1587-1605.
19. Snell GD. The H-2 locus of the mouse: observations and speculations concerning its comparative genetics and its polymorphism. Folia Biologica (Praha) 1968; 14: 335-358.
20. Zijlstra M, Vasmel WL, Radaskiewicz T, Matthews E, Melief CJ. The H-2 complex regulates both the susceptibility to mouse viral lymphomagenesis and the phenotype of the virus-induced lymphomas. [Review]. Journal of Immunogenetics 1986; 13: 69-76.
21. Demant P, Oomen LC, Oudshoorn Snoek M. Genetics of tumor susceptibility in the mouse: MHC and non-MHC genes. Advances in Cancer Research 1989; 53: 117-179.
22. Lonai P, Katz E, Haran Ghera N. Role of the major histocompatibility complex in resistance to viral leukemia; its effect on the preleukemic stage of leukemogenesis. Springer Seminars in Immunopathology 1982; 4: 373-396.
23. Zijlstra M, Melief CJ. Virology, genetics and immunology of murine lymphomagenesis. [Review]. Biochimica et Biophysica Acta 1986; 865: 197-231.
24. Xu A, van Eijk MJ, Park C, Lewin HA. Polymorphism in BoLA-DRB3 exon 2 correlates with resistance to persistent lymphocytosis caused by bovine leukemia virus. Journal of Immunology 1993; 151: 6977-6985.
25. Heinzelmann EW, Zsigray RM, Collins WM. Cross-reactivity between RSV-induced tumor antigen and B5 MHC alloantigen in the chicken. Immunogenetics 1981; 13: 29-37.
26. Han R, Breitburd F, Marche PN, Orth G. Linkage of regression and malignant conversion of rabbit viral papillomas to MHC class II genes. Nature 1992; 356: 66-68.
27. Albright AL, Gill TJI, Geyer SJ. Immunogenetic control of brain tumor growth in rats. Cancer Research 1977; 37: 2512-2521.
28. Rao KN, Shinozuka H, Kunz HW, Gill TJI. Enhanced susceptibility to a chemical carcinogen in rats carrying MHC-linked genes influencing development (GRC). International Journal of Cancer 1984; 34: 113-120.
29. Melhem MF, Rao KN, Kunz HW, Kazanecki M, Gill TJI. Genetic control of susceptibility to diethylnitrosamine carcinogenesis in inbred ACP (grc+) and R16 (grc) rats. Cancer Research 1989; 49: 6813-6821.
30. Melhem MF, Kunz HW, Gill TJI. Genetic control of susceptibility to diethylnitrosamine and dimethylbenzanthracene carcinogenesis in rats. American Journal of Pathology 1991; 139: 45-51.
31. Melhem MF, Kunz HW, Gill TJI. A major histocompatibility complex-linked locus in the rat critically influences resistance to diethylnitrosamine carcinogenesis. Proceedings of the National Academy of Sciences U S A 1993; 90: 1967-1971.
32. Lu D, Kunz HW, Melhem MF, Gill TJI. Cell lines from grc congenic strains of rats having different susceptibilities to chemical carcinogens. Cancer Research 1993; 53: 4089-4095.
33. Gill TJI, Kunz HW. Gene complex controlling growth and fertility linked to the major histocompatibility complex in the rat. American Journal of Pathology 1979; 96: 185-206.
34. Gill TJI. The borderland of embryogenesis and carcinogenesis. Major histocompatibility complex-linked genes affecting development and their possible relationship to the development of cancer. Biochimica et Biophysica Acta 1984; 738: 93-102.
35. Gill TJI. Role of the major histocompatibility complex region in reproduction, cancer, and autoimmunity. American Journal of Reproductive Immunology 1996; 35: 211-215.
36. Le Bouteiller P. HLA class I chromosomal region, genes, and products: facts and questions. Critical Reviews in Immunology 1994; 14: 89-129.
37. Gill TJI, Natori T, Salgar SK, Kunz HW. Current status of the major histocompatibility complex in the rat. Transplantation Proceedings 1995; 27: 1495-1500.
38. Mirsky ML, Olmstead C, Da Y, Lewin HA. Reduced bovine leukemia virus proviral load in genetically resistant cattle. Animal Genetics 1998; 29: 245-252.
39. Stear MJ, Dimmock CK, Newman MJ, Nicholas FW. BoLA antigens are associated with increased frequency of persistent lymphocytosis in bovine leukemia virus infected cattle and with increased incidence of antibodies to bovine leukemia virus. Animal Genetics 1988; 19: 151-158.
40. van Eijk MJ, Stewart-Haynes JA, Beever JE, Fernando RL, Lewin HA. Development of persistent lymphocytosis in cattle is closely associated with DRB2. Immunogenetics 1992; 37: 64-68.
41. Zanotti M, Poli G, Ponti W, et al. Association of BoLA class II haplotypes with subclinical progression of bovine leukemia virus infection in Holstein-Friesian cattle. Animal Genetics 1996; 27: 337-341.
42. Kaufman J, Milne S, Gobel TWF, et al. The chicken B locus is a minimal essential major histocompatibility complex. Nature 1999; 401: 923-925.
43. Briles WE, Briles RW, Taffs RE. Resistance to a malignant disease in chickens is mapped to a subregion of major histocompatibility (B) complex. Science 1983; 219: 977-979.
44. Hepkema BG, Blankert JJ, Albers GA, et al. Mapping of susceptibility to Marek's disease within the major histocompatibility (B) complex by refined typing of White Leghorn chickens. Animal Genetics 1993; 24: 283-287.
45. Schat KA, Taylor RL, Jr., Briles WE. Resistance to Marek's disease in chickens with recombinant haplotypes to the major histocompatibility (B) complex. Poultry Science 1994; 73: 502-508.
46. Sato K, Abplanalp H, Napolitano D, Reid J. Effects of heterozygosity of major histocompatibility complex haplotypes on performance of Leghorn hens sharing a common inbred background. Poultry Science 1992; 71: 18-26.
47. Collins WM, Briles WE, Zsigray RM, et al. The B locus (MHC) in the chicken: association with the fate of RSV-induced tumors. Immunogenetics 1977; 5: 333-343.
48. Plach J, Jurajda V, Benda V. Resistance to Marek's disease is controlled by a gene within the B-F region of the chicken major histocompatibility complex in Rous sarcoma regressor or progressor inbred lines of chickens. Folia Biologica (Praha) 1984; 30: 251-258.
49. Plach J, Benda V. Location of the gene responsible for Rous sarcoma regression in the B-F region of the B complex (MHC) of the chicken. Folia Biologica (Praha) 1981; 27: 363-368.
50. Bacon LD, Crittenden LB, Witter RL, Fadly A, Motta J. B5 and B15 associated with progressive Marek's disease, Rous sarcoma, and avian leukosis virus-induced tumors in inbred 15I4 chickens. Poultry Science 1983; 62: 573-578.
51. Martin A, Dunnington EA, Briles WE, Briles RW, Siegel PB. Marek's disease and major histocompatibility complex haplotypes in chickens selected for high or low antibody response. Animal Genetics 1989; 20: 407-414.
52. Pinard MH, Janss LL, Maatman R, Noordhuizen JP, van der Zijpp AJ. Effect of divergent selection for immune responsiveness and of major histocompatibility complex on resistance to Marek's disease in chickens. Poultry Science 1993; 72: 391-402.
53. Collins WM, Dunlop WR, Zsigray RM, Briles RW, Fite RW. Metastasis of Rous sarcoma tumors in chickens is influenced by the major histocompatibility (B) complex and sex. Poultry Science 1986; 65: 1642-1648.
54. Bacon LD. Influence of the major histocompatibility complex on disease resistance and productivity. Poultry Science 1987; 66: 802-811.
55. Collins WM, Brown DW, Ward PH, Dunlop WR, Briles WE. MHC and non-MHC genetic influences on Rous sarcoma metastasis in chickens. Immunogenetics 1985; 22: 315-321.
56. Collins WM, Zervas NP, Urban WE, Jr., Briles WE, Aeed PA. Response of B complex haplotypes B22, B24, and B26 to Rous sarcomas. Poultry Science 1985; 64: 2017-2019.
57. Brown DW, Collins WM, Ward PH, Briles WE. Complementation of major histocompatibility haplotypes in regression of Rous sarcoma virus-induced tumors in noninbred chickens. Poultry Science 1982; 61: 409-413.
58. Schierman LW, Collins WM. Influence of the major histocompatibility complex on tumor regression and immunity in chickens. Poultry Science 1987; 66: 812-818.
59. Plachy J, Pink JR, Hala K. Biology of the chicken MHC (B complex). Critical Reviews in Immunology 1992; 12: 47-79.
60. Heinzelmann EW, Zsigray RM, Collins WM. Increased growth of RSV-induced tumors in chickens partially tolerant to MHC alloantigens. Immunogenetics 1981; 12: 275-284.
61. Yoo BH, Sheldon BL. Association of the major histocompatibility complex with avian leukosis virus infection in chickens. British Poultry Science 1992; 33: 613-620.
62. Benacerraf B, McDevitt HO. Histocompatibility-linked immune response genes. Science 1972; 175: 273-279.
63. Bodmer WF. Evolutionary significance of the HLA system. Nature 1972; 237: 139-145.
64. Cuzick J. Molecular epidemiology: carcinogens, DNA adducts, and cancer - still a long way to go. Journal of the National Cancer Institute 1995; 87: 861-862.
65. Dausset J. The major histocompatibility complex in man. Science 1981; 213: 1469-1474.
66. Amiel JL. Study of the leukocyte phenotypes in Hodgkin's disease. In: Curtoni ES, Mattiuz PL, Tosi RM, eds. Histocompatibility Testing 1967, Copenhagen: Munksgaard, 1967: 79-81.
67. Walford RL, Finkelstein S, Neerhout R, Konrad P, Shanbrom E. Acute childhood leukemia in relation to the HL-A human transplantation genes. Nature 1970; 5231: 461-462.
68. Albert ED, Nisperos B, Thomas ED. HLA antigens and haplotypes in acute leukemia. Leukemia Research 1977; 1: 261-269.
69. Tiwari JL, Terasaki PI. HLA and Disease Associations. New York: Springer-Verlag, 1985;
70. de Moerloose P, Chardonnens X, Vassalli P, Jeannet M. [HL-A D antigens from B-lymphocytes and susceptibility to certain diseases]. Schweizerische Medizinische Wochenschrift - Journal Suisse De Medecine 1977; 107: 1461-1461.
71. Von Fliedner VE, Sultan-Khan Z, Jeannet M. HLA-DRw antigens associated with acute leukemia. Tissue Antigens 1980; 16: 399-404.
72. Casper JT, Duquesnoy RJ, Borella L. Transient appearance of HLA-DRw-positive leukocytes in peripheral blood after cessation of antileukemia therapy. Transplantation Proceedings 1980; 12: 130-133.
73. de Jongh BM, van der Dose-van den Berg A, Schreuder GM. Random HLA-DR distribution in children with acute lymphocytic leukemia in long-term continuous remission. British Journal of Haematology 1982; 52: 161-163.
74. Caruso C, Cammarata G, Sireci G, Modica MA. HLA-Cw4 association with acute lymphoblastic leukemia in Sicilian patients. Vox Sang 1988; 54: 57-58.
75. Orgad S, Cohen IJ, Neumann Y, et al. HLA-A11 is associated with poor prognosis in childhood acute lymphoblastic leukemia (ALL). Leukemia 1988; 2: 79S-87S.
76. Michel K, Hubbel C, Dock NL, Davey FR. Correlation of HLA-DRw3 with childhood acute lymphocytic leukemia [letter]. Archives of Pathology & Laboratory Medicine 1981; 105: 560-560.
77. D'Amaro J, Bach FH, van Rood JJ, Rimm AA, Bortin MM. HLA C associations with acute leukemia. Lancet 1984; 2: 1176-1178.
78. Bortin MM, D'Amaro J, Bach FH, Rimm AA, van Rood JJ. HLA associations with leukemia. Blood 1987; 70: 227-232.
79. Muller CA, Hasmann R, Grosse Wilde H, et al. Significant association of acute lymphoblastic leukemia with HLA- Cw7. Genetic Epidemiology 1988; 5: 453-461.
80. Navarrete C, Alonso A, Awad J, et al. HLA class I and class II antigen associations in acute leukemias. Journal of Immunogenetics 1986; 13: 77-84.
81. Dyer PA, Ridway JC, Flanagan NG. HLA-A,B and DR antigens in chronic lymphocytic leukemia. Disease Markers 1986; 4: 231-237.
82. Seremetis S, Cuttner J, Winchester R. Definition of a possible genetic basis for susceptibility to acute myelogenous leukemia associated with the presence of a polymorphic Ia epitope. Journal of Clinical Investigation 1985; 76: 1391-1397.
83. Caruso C, Lo Campo P, Botindari C, Modica MA. HLA antigens in Sicilian patients affected by chronic myelogenous leukemia. Journal of Immunogenetics 1987; 14: 295-299.
84. Linet MS, Bias WB, Dorgan JF, McCaffrey LD, Humphrey RL. HLA antigens in chronic lymphocytic leukemia. Tissue Antigens 1988; 31: 71-78.
85. Dorak MT, Chalmers EA, Gaffney D, et al. Human major histocompatibility complex contains several leukemia susceptibility genes. Leukemia & Lymphoma 1994; 12: 211-222.
86. Dorak MT, Owen G, Galbraith I, et al. Nature of HLA-associated predisposition to childhood acute lymphoblastic leukemia. Leukemia 1995; 9: 875-878.
87. Dorak MT, Machulla HK, Hentschel M, Mills KI, Langner J, Burnett AK. Influence of the major histocompatibility complex on age at onset of chronic lymphoid leukemia. International Journal of Cancer 1996; 65: 134-139.
88. Dearden SP, Taylor GM, Gokhale DA, et al. Molecular analysis of HLA-DQB1 alleles in childhood common acute lymphoblastic leukemia. British Journal of Cancer 1996; 73: 603-609.
89. Ghodsi K, Taylor GM, Gokhale DA, et al. Lack of association between childhood common acute lymphoblastic leukemia and an HLA-C locus dimorphism influencing the specificity of natural killer cells. British Journal of Haematology 1998; 102: 1279-1283.
90. Budowle B, Acton RT, Barger BO, et al. Properdin factor B and acute lymphocytic leukemia (ALL). Cancer 1982; 50: 2369-2371.
91. Dorak MT, Lawson T, Machulla HKG, Darke C, Mills KI, Burnett AK. Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia. Blood 1999; 94: 694-700.
92. Chan KW, Pollack MS, Braun D, Jr., O'Reilly RJ, Dupont B. Distribution of HLA genotypes in families of patients with acute leukemia. Implications for transplantation. Transplantation 1982; 33: 613-615.
93. Dorak MT, Burnett AK, Worwood M. Thymus-leukemia antigens: the haemochromatosis gene product? Immunology & Cellular Biology 1994; 72: 435-439.
94. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics 1996; 13: 399-408.
95. Dorak MT, Sproul AM, Gibson BE, Burnett AK, Worwood M. The C282Y mutation of HFE is another male-specific risk factor for childhood ALL [letter]. Blood 1999; 94: 3957 [www].
96. De Moor P, Louwagie A. Distribution of HLA genotypes in sibs of patients with acute leukemia. Scandinavian Journal of Haematology 1985; 34: 68-70.
97. De Moor P. Distribution of HLA genotypes in sibs of patients with acute lymphoblastic leukemia. European Journal of Haematology 1989; 42: 317-318.
98. Carpentier NA, Jeannet M. Increased HLA-DR compatibility between patients with acute myeloid leukemia and their parents: implication for bone marrow transplantation. Transplantation Proceedings 1987; 19: 2644-2645.
99. Von Fliedner VE, Merica H, Jeannet M, et al. Evidence for HLA-linked susceptibility factors in childhood leukemia. Human Immunology 1983; 8: 183-193.
100. Werner-Favre C, Jeannet M. HLA compatibility in couples with children suffering from acute leukemia or aplastic anemia. Tissue Antigens 1979; 13: 307-309.
101. McSween JM, Fernandez LA, Eastwood SL, Pyasmary AF. Restricted genetic heterogeneity in acute lymphocytic leukemia. Tissue Antigens 1980; 16: 70-72.
102. Nordlander C, Fuchs T, Hammarstrom L, Smith CI. Human leukocyte antigens group A in couples with unexplained infertility. Fertility & Sterility 1983; 40: 60-65.
103. Dorak MT, Burnett AK. Major histocompatibility complex, t-complex, and leukemia [Review]. Cancer Causes & Control 1992; 3: 273-282.
104. Shin HS, Bennett D, Artzt K. Gene mapping within the T/t complex of the mouse. IV: The inverted MHC is intermingled with several t-lethal genes. Cell 1984; 39: 573-578.
105. Artzt K. Gene mapping within the T/t complex of the mouse. III: t-Lethal genes are arranged in three clusters on chromosome 17. Cell 1984; 39: 565-572.
106. Fox HS, Martin GR, Lyon MF, et al. Molecular probes define different regions of the mouse t complex. Cell 1985; 40: 63-69.
107. Silver LM, Remis D. Five of the nine genetically defined regions of mouse t haplotypes are involved in transmission ratio distortion. Genetical Research 1987; 49: 51-56.
108. Silver LM. Gene dosage effects on transmission ratio distortion and fertility in mice that carry t haplotypes. Genetical Research 1989; 54: 221-225.
109. Albert ED, Mickey MR, Ting A, Terasaki PI. Deduction of 2140 HL-A haplotypes and segregation analysis in 535 families. Transplantation Proceedings 1973; 5: 215-221.
110. Komlos L, Livni E, Klein T, Halbrecht I, Hart J, Zaizov R. Distortion in the parental transmission of HLA-A2 haplotypes (locus A,B). Medical Hypotheses 1993; 41: 513-515.
111. Komlos L, Korostishevsky M, Halbrecht I, Vardimon D, Ben-Rafael Z, Klein T. Possible sex-correlated transmission of maternal class I HLA haplotypes. European Journal of Immunogenetics 1997; 24: 169-177.
112. Feingold N, Degos L, Feingold J. HLA in populations: an approach for genetical susceptibility to cancer. Journal of Immunogenetics 1979; 6: 29-35.
113. Guardiola J, Maffei A. Control of MHC class II gene expression in autoimmune, infectious, and neoplastic diseases. Critical Reviews in Immunology 1993; 13: 247-268.
114. Concha A, Esteban F, Cabrera T, Ruiz-Cabello F, Garrido F. Tumor aggressiveness and MHC class I and II antigens in laryngeal and breast cancer. Seminars in Cancer Biology 1991; 2: 47-54.
115. Brunner CA, Gokel JM, Riethmuller, Johnson JP. Expression of HLA-D subloci DR and DQ by breast carcinomas is correlated with distinct parameters of favorable prognosis. European Journal of Cancer 1991; 27: 411-416.
116. Sheen-Chen SM, Chou FF, Eng HL, Chen WJ. An evaluation of the prognostic significance of HLA-DR expression in axillary-node-negative breast cancer. Surgery 1994; 116: 510-515.
117. Cromme FV, van Bommel PF, Walboomers JM, et al. Differences in MHC and TAP-1 expression in cervical cancer lymph node metastases as compared with the primary tumors. British Journal of Cancer 1994; 69: 1176-1181.
118. Garrido F, Cabrera T, Concha A, Glew S, Ruiz-Cabello F, Stern PL. Natural history of HLA expression during tumor development. [Review]. Immunology Today 1993; 14 : 491-499.
119. Garrido F, Cabrera T, Lopez-Nevot MA, Ruiz-Cabello F. HLA class I antigens in human tumors. Advances in Cancer Research 1995; 67: 155-195.
120. Browning M, Petronzelli F, Bicknell D, et al. Mechanisms of loss of HLA class I expression on colorectal tumor cells. Tissue Antigens 1996; 47: 364-371.
121. Duggan-Keen MF, Keating PJ, Stevens FR, et al. Immunogenetic factors in HPV-associated cervical cancer: influence on disease progression. European Journal of Immunogenetics 1996; 23: 275-284.
122. Bontkes H, Walboomers JM, Meijer CJ, Helmerhorst TJ, Stern PL. Specific HLA class I down-regulation is an early event in cervical dysplasia associated with clinical progression [letter]. Lancet 1998; 351: 187-188.
123. Kaklamanis L, Leek R, Koukourakis M, Gatter KC, Harris AL. Loss of transporter in antigen processing 1 transport protein and major histocompatibility complex class I molecules in metastatic versus primary breast cancer. Cancer Research 1995; 55: 5191-5194.
124. Marincola FM, Shamamian P, Alexander RB, et al. Loss of HLA haplotype and B locus down-regulation in melanoma cell lines. Journal of Immunology 1994; 153: 1225-1237.
125. Morris A. Modification of histocompatibility antigen expression in cells expressing activated oncogenes: implications for tumor development. Anticancer Research 1990; 10: 1161-1167.
126. Howcroft TK, Richardson JC, Singer DS. MHC class I gene expression is negatively regulated by the proto-oncogene, c-jun. EMBO Journal 1993; 12: 3163-3169.
M. Tevfik Dorak, MD, PhD
Last edited on 22 September 2007