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MHC and Leukemia

M. Tevfik Dorak, MD, PhD

PowerPoint presentation on MHC & Leukemia Associations in Humans

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.

Animal experiments

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-2^{k 4;5}. In 1964, Lilly et al, convincingly showed the role of the H-2^k haplotype on the development of leukemia by inoculating leukemic extracts into mice from segregating generations with different H-2 types ⁶. The H-2^k 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-2^k as much as virus-induced leukemia ^7;8. In Lilly's studies, the H-2^k 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-2^b/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-2^k 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-2^k haplotype has no effect on leukemogenesis in mice. Reviews of earlier studies concluded that the studies where the H-2^b 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-A^k/k) developed T-cell lymphoma with a mean latency period of 37 weeks. In resistant strains (H-2^b/b or H-2^b/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-2^b-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.

Human studies

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

HLA-A2; HLA-Cw3, -Cw4; HLA-DR53, HLA-DPB1*0201

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)

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M. Tevfik Dorak, MD, PhD

Last edited on 22 September 2007

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