Genetic variation in hla and susceptibility to acute myeloid leukemia

Genetic variation in HLA and susceptibility to acute myeloid leukemia
Claudia Rizzo^1,2, Giulia Accardi², Calogero Caruso^1,2
1Unit of Transfusion Medicine, University Hospital and ²Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo .

Running Title: HLA and Leukemia

Prof. Calogero Caruso MD

Sezione di Patologia generale

Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi

Corso Tukory 211

90134 Palermo

Phone + 390916555911

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Key words: HLA, KIR, AML
In this issue of Acta Haematologica, Authors report the association between the Human Major Histocompatibility complex (MHC) HLA-C3 and Acute Myeloid Leukemia (AML) in Korean population, confirming previous studies on association between HLA-C and AML (1). Following the demonstration by Lilly and colleagues, in 1964, of the increased risk of spontaneous or virus-induced leukemia in congenic mice with the H-2K (the MHC in mice), it is now over forty years since the first associations between particular HLA antigens and leukemia and lymphoma diseases were described, including a cross-reactive group of HLA-B antigens and Hodgkin’s disease, HLA-A2 and acute lymphocytic leukemia (ALL) (2). Over the time, a lot of studies on the association between HLA and the different kinds of leukemia have been performed with contrasting results (2). Following, these pioneering studies, a broad spectrum of immune-mediated diseases, certain malignancies, longevity, infectious diseases and adverse reactions to some drug have been shown to be associated with allelic variants of HLA (3,4). So far, there appear to be no striking leukemia genetic susceptibility loci in HLA similar in nature and magnitude to those seen for autoimmune and infectious diseases. However, mounting evidence suggests that more modestly associated susceptibility loci showing population and type may exist (1,2). Nevertheless, the clear identification of a causative role for HLA polymorphism in the pathogenesis of HLA-associated leukemia remains the exception rather than the rule. However, advances in a full understanding of MHC biological functions should be going to permit comprehensive and definitive studies in evaluating HLA role in leukemia.

The human MHC is a multi-gene including the highly polymorphic HLA Class I (HLA-A, -B, -C) and II genes (HLA-DRA, -DRB1, -DRB3-5, -DQA, -DQB, -DPA, -DPB) that code different kinds of glycoproteins specialized in presentation of short peptides derived from infectious agents or self proteins to T lymphocytes, hence playing a key role in both cellular and humoral immune response. This occurs through signalling to T cell receptors (TCR) and subsequent initiation of the acquired immune response. Their polymorphism impacts on peptide-binding groove, varying the amino acids that can be housed within the peptide-binding pockets. Thus, different HLA alleles possess different peptide-binding repertoires. HLA class I proteins present peptides from intra-cellular proteins (including invasive viruses) to TCR on CD8 (cytotoxic) T cells leading to immune mechanisms which destroy the cell. It is noteworthy that HLA proteins, in particular HLA-C alleles, also interact with killer immunoglobulin-like receptors (KIR) that play a crucial role in the activity of natural killer cells, known to control tumour transformation and viral infection. The peptide binding groove of HLA class II proteins, only expressed on antigen presenting cells, carries a self or non-self peptide derived from proteins sourced from outside the cell by endocytosis. Then, it is presented to TCR of CD4 (helper) T cells. Besides, there is a wide variety of genes in extended HLA genes, some with a role in immunity, some with non-immune roles and many with unidentified roles. The occurrence together of two or more alleles at a frequency other than expected by chance is termed allelic association or linkage disequilibrium and there is strong linkage disequilibrium between several of the extended HLA loci (3,5).

Taking into account the complexity and the function of HLA, which are the mechanisms responsible for association between leukemia and HLA, if any? Most of the performed studies present serious challenges because of a number of confounding factors: i) the sample size of most studies which are prone to selection bias and false positive associations. In fact, a minimum size of 320 persons for each sample is required to detect the difference in frequency if an antigen occurs, for example, in 5% of sample A and in 15% of sample; ii) in the different studies there are different inclusion criteria, inappropriate mixing of data (cohort effects) referred to people of different age, inappropriate control matching i.e. lack of selection from the same target population; iii) correction to adjust for multiple comparisons is not used in several studies (we do not need them only in confirmatory studies); iv) linkage disequilibrium i.e. the associated HLA polymorphism may play no direct role, and the actual disease-predisposing polymorphism may be in linkage disequilibrium with the initially reported HLA association, which merely acts as a marker (4).

However, concerning the possible role of HLA molecules in leukemia, a causative role of HLA in terms of presentation of a nonself-peptide (i.e. virus) or altered-self-peptide (i.e. mutated oncogene) is a possibility. An alternative, not mutually exclusive possibility refers to a causative role via influence on the T-cell repertoire, including Treg cells (2,3). On the other hand, no significant evidence exist for the association with non HLA loci in extended MHC (1,2)

It is noteworthy that, a recent in-depth investigation of KIR genes and their cognate HLA ligands on childhood ALL risk, carried out in 212 childhood ALL cases and 231 healthy controls, suggest a role for KIR genes and their HLA ligands in childhood ALL aetiology that may vary among ethnic groups (6).

So, in our opinion, the observed association between HLA Class I antigen, in particular with HLA-C alleles, can be explained by their role as ligands for KIR. The negative results obtained might be due to the fact that HLA-C gene is highly polymorphic and more than thousand different proteins have been identified so far, hence a two digit HLA-C typing is not accurate enough to predict which KIR/KIR ligand interaction occurs. In addition, HLA-C bound peptides play a role in KIR/KIR-L interactions, as not all the presented peptides seem to be permissive to KIR interaction (5)

The accurate characterization of HLA-C allotypes, in future studies, will be crucial to clarify this point.

ACKNOWLEDGEMENTS

C.R. is a PhD student of the PhD course directed by C.C.

REFERENCES

1) Acute myeloid leukemia is a disease associated with HLA-C3

2) Urayama KY, Thompson PD, Taylor M, Trachtenberg EA, Chokkalingam AP: Genetic variation in the extended major histocompatibility complex and susceptibility to childhood acute lymphoblastic leukemia: a review of the evidence. Front Oncol 2013;3:300.

3) Dyer P, McGilvray R, Robertson V, Turner D: Status report from 'double agent HLA': health and disease. Mol Immunol. 2013;55:2-7

4) Caruso C, Candore G, Romano GC, Lio D, Bonafè M, Valensin S, Franceschi C. Immunogenetics of longevity. Is major histocompatibility complex polymorphism relevant to the control of human longevity? A review of literature data. Mech Ageing Dev 2001; 30;122:445-62.

5)Falco M, Moretta L, Moretta A, Bottino C. KIR and KIR ligand polymorphism: a new area for clinical applications? Tissue Antigens. 2013;82:363-73

6) de Smith AJ, Walsh KM, Ladner MB, Zhang S, Xiao C, Cohen F, Moore TB, Chokkalingam AP, Metayer C, Buffler PA, Trachtenberg EA, Wiemels JL. The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia. Blood. 2014;123:2497-503