Immunogenetic risk factors for oncohematological diseases”

HLA (Human Leukocyte Antigens) genes play a key role in regulating the antitumor immune response and are characterized by significant allelic and population polymorphism. Molecules encoded by HLA genes are involved in the selection of the T cell receptor repertoire, the processing and presentation of neoantigens to T cells, and the regulation of the cytolytic activity of natural killer cells. The structural features of HLA antigens, and especially the characteristics of the antigen-binding site, determine the effectiveness of their interaction with immunocompetent cells, mediating an individual’s susceptibility or resistance to various diseases, including malignancies. Tumor cell evasion of immune control and their unlimited proliferation may result from structural or functional changes in HLA molecules, leading to blockage of neoantigen presentation to cytotoxic T lymphocytes. The causes of such changes may be mutations in the genes encoding the a-chain of HLA class I molecules, the aand b-chains of HLA class II molecules, as well as in the genes encoding the synthesis of proteins necessary for the proper assembly, transport, expression and functions of HLA molecules (for example, b2-microglobulin or the invariant chain of HLA class II molecules). Low or lost expression of HLA molecules on tumor cells also contributes to decreased immune surveillance. Another factor determining the effectiveness of antitumor surveillance is “HLA diversity.” Homozygosity of HLA genes narrows the spectrum of neoantigens that can be presented to cytotoxic T cells, weakening antitumor control. This review analyzes HLA genetic factors associated with the risk of developing a number of hematologic malignancies (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and diffuse large B cell lymphoma) in various population groups. HLA markers associated with the response to therapy and long-term prognosis of certain hematologic malignancies are identified. The results of the study of the associations between the HLA phenotype and hematologic malignancies can be used in practice as additional differential diagnostic or prognostic criteria, as well as for the formation of risk groups for developing these diseases.

1. Aggressive nonfollicular lymphomas – diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt’s lymphoma. 2021. [Electronic resource]. Available at: https://oncology-association.ru/wp-content/uploads/2021/03/v-kletochnaya-2021.pdf (date of access: October 27, 2025).

2. Biderman B.V., Likold E.B., Abdrakhimova A.R., Leonov E.A., Khamaganova E.G., Sudarikov A.B. HLA allele repertoire in Russian chronic lymphocytic leukemia patients with an unfavorable prognosis. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfusiology, 2020, Vol. 65, no. 3, pp. 312-320. (In Russ.)

3. Gayfullina R.F., Galiullin A.N., Burykin I.M. Risk factors of the occurrence and development of hematological malignancies (Literature review). Obschestvennoye zdorovye zdravookhranenie = Public Health and Health Care, 2024, no 1, pp. 16-25. (In Russ.)

4. Malignant neoplasms in Russia in 2023 (incidence and mortality) / edited by Kaprin A.D., Starinsky V.V., Shakhzadova A.O.] Moscow: P.A. Herzen Moscow Oncology Research Institute − branch of the National Medical Research Center of Radiology of the Ministry of Health of Russia, 2024, 276 p.

5. Acute lymphoblastic leukemia: Clinical guidelines of the Ministry of Health of the Russian Federation [Electronic resource]. Moscow, 2020. 122 p. Available at: https://oncology-association.ru/wp-content/uploads/2020/09/oll.pdf (date of access: October 27, 2025).

6. Acute myeloid leukemia: Clinical guidelines of the Ministry of Health of the Russian Federation [Electronic resource]. Moscow, 2022. 443 p. Available at: https://oncology-association.ru/wp-content/uploads/2022/05/oml.pdf (date of access: October 27, 2025).

7. Khamaganova E.G., Aleschenko S.M., Murashova L., Zaretskaya Y.M. Immunogenetic Factors of Predisposition to Blood Malignancies in Russian Population. Rossiyskiy immunologicheskiy zhurnal = Russian Journal of Immunology, 2001, Vol. 6, no. 3, pp. 265-270. (In Russ.)

8. Chronic lymphocytic leukemia / small lymphocytic lymphoma: Clinical guidelines of the Ministry of Health of the Russian Federation [Electronic resource]. Moscow, 2022. 101 p. Available at: https:// oncology-association.ru/wp-content/uploads/2022/06/hronicheskij-limfoczitarnyj-lejkoz-1.pdf (date of access: October 27, 2025).

9. Chronic myeloid leukemia: Clinical guidelines of the Ministry of Health of the Russian Federation [Electronic resource]. Moscow, 2022. 85 p. Available at: https://oncology-association.ru/wp-content/uploads/2022/04/hronicheskij-mieloidnyjlejkoz.pdf (date of access: October 27, 2025).

10. Alcoceba M., Sebastián E., Marín L., Balanzategui A., Sarasquete M.E., Chillón M.C., Jiménez C., Puig N., Corral R., Pardal E. HLA specificities are related to development and prognosis of diffuse large B-cell lymphoma. Blood, 2013, Vol. 122, no. 8, pp. 1448-1454.

11. Cao S., Wu Y., Qian X., Ma H. Genetic variants in HLA-DP/DQ contribute to risk of acute myeloid leukemia: A case-control study in Chinese. Pathol. Res. Pract., 2020, Vol. 216, no. 3, 152829. doi: 10.1016/j.prp.2020.152829.

12. Cerhan J.R., Berndt S.I., Vijai J., Ghesquières H., McKay J., Wang S.S., Wang Z., Yeager M., Conde L., de Bekker P.I.W. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat. Genet., 2014, Vol. 46, no. 11, pp. 1233-1238.

13. Choi H.B., Roh S.Y., Choi E.J., Yoon H.Y., Kim S.Y., Hong Y.S., Kim D.W., Kim T.G. Association of HLA alleles with non-Hodgkin’s lymphoma in Korean population. Int. J. Hematol., 2008, Vol. 87, no. 2, pp. 203-209.

14. Diamanti I., Fylaktou A., Verrou E., Vlachaki E., Sinakos M., Katodritou E., Ouranos K., Minti F., Gioula G. HLA variations in patients with diffuse large B-cell lymphoma and association with disease risk and prognosis: a case-control study. Front. Genet., 2024, Vol. 15, 1341822. doi: 10.3389/fgene.2024.1341822.

15. Dorak M.T., Oguz F.S., Yalman N., Diler A.S., Kalayoglu S., Anak S., Sargin D., Carin M. A male-specific increase in the HLA-DRB4 (DR53) frequency in high-risk and relapsed childhood ALL. Leuk. Res., 2002, Vol. 26, no. 7, pp. 651-656.

16. Fangazio M., Ladewig E., Gomez K., Garsia-Ibanez L., Kumar R., Teruya-Feldstein J., Rossi D., Filip I., Pan-Hammarström Q., Inghirami G. Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma. Proc. Natl. Acad. Sci. USA, 2021, Vol. 118, no. 22, e2104504118. doi: 10.1073/pnas.2104504118.

17. Fernández-Torres J., Flores-Jiménez D., Arroyo-Pérez A., Granados J., Lopez-Reyes A. HLA-B*40 allele plays a role in the development of acute leukemia in Mexican population: a case-control study. Biomed Res. Int., 2013, 705862. doi: 10.1155/2013/705862.

18. Kazemi M.H., Momeni-Varposhti Z., Roshandel E., Sankanian G., Rouzbahani N.H., Ghorban K., Rajaeinejad M., Hajifathali A. Association of HLA alleles with hematologic malignancies. Gene Rep., 2021, Vol. 24, 101346. doi: 10.1016/j.genrep.2021.101346.

19. Kirtane K., Lee S.L. Racial and ethnic disparities in hematologic malignancies. Blood, 2017, Vol. 130, no.15, pp. 1699-1705.

20. Lu Y., Abdou A.M., Cerhan J.R., Morton L.M., Severson R.K., Davis S., Cozen W., Rothman N., Bernstein L., Chanock S., Hartge P., Wang S.S. Human leukocyte antigen class I and II alleles and overall survival in diffuse large B-cell lymphoma and follicular lymphoma. Sci. World J., 2011, Vol. 11, pp. 2062-2070.

21. Mishra V.C., Deshpande T., Gupta N., Dorwal P., Chandra D., Raina V., Sharma G. Frequency analysis of HLA-B allele in leukemia patients from a North Indian population: A case-control study. Meta Gene, 2021, Vol. 27, 100842. doi: 10.1016/j.mgene.2020.100842.

22. Rodrigues Fernandes T.A., Fukai R., Souza C.A., Lorand-Metze I., Magna L.A., Standler Kraemer M.H. Molecular identification of the HLA-DRB1-DQB1 for diagnosis and follow-up of acute leukemias. Blood Cells Mol. Dis., 2010, Vol. 44, no. 2, pp. 69-73.

23. Sewastianik T., Roy C., Gormally M.V., Montesion M., Halvey P., Jindal A., Lam H., Schoenfeld A., Klebanoff C.A., Opiteck G.J., Nagorsen D. Allele-specific HLA LOH in solid tumors: distinct patterns by tumor type and potential prognostic relevance. J. Immunother. Cancer, 2025, Vol. 13, no. 9, e012435. doi: 10.1136/jitc-2025-012435.

24. Shah N., Decker W.K., Lapushin R., Xing D., Robinson S.N., Yang H., Parmar S., Tung S.S., O’Brien S., Fernandez-Viña M., Shpall E.J., Wierda W.G. HLA homozygosity and haplotype bias among patients with chronic lymphocytic leukemia: implications for disease control by physiological immune surveillance. Leukemia, 2011, Vol. 25, no. 6, pp. 1036-1039.

25. Uçar F., Sönmez M., Erkut N., Balcı M., Yücel B., Yılmaz M., Erduran E., Ovalı E. Relation of HLA-A,-B,- DRB1 alleles and haplotypes in patients with acute leukemia: a case control study. Arch. Med. Res., 2011, Vol. 42, no. 4, pp. 305-310.

26. Ureshino H., Shindo T., Tanaka H., Hiroh Saji H., Kimura S. HLA Polymorphisms are associated with treatment-free remission following discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia. Mol. Cancer Ther., 2021, Vol. 20, no. 1, pp. 142-149.

27. Wang S.S., Abdou A.M., Morton L.M., Thomas R., Cerhan J.R., Gao X., Cozen W., Rothman N., Davis S., Severson R.K., Bernstein L., Hartge P., Carrington M. Human leukocyte antigen class I and II alleles in non-Hodgkin lymphoma etiology. Blood, 2010, Vol. 115, no. 23, pp. 4820-4823.

28. Wang S.S., Carrington M., Berndt S.I., Slager S.L., Bracci P.M., Voutsinas J., Cerhan J.R., Smedby K.E., Hjalgrim H., Vijai J. HLA Class I and II diversity contributes to the etiologic heterogeneity of non-hodgkin lymphoma subtypes. Cancer Res., 2018, Vol. 78, no. 14, pp. 4086-4096.

29. Xiao H., He J., Liang S., Cai D., Zhou Q., Liu L., Yan X., Chi J., Xiao Q., Wang L. Racial/ethnic disparities on the risk of second malignant neoplasm among Hodgkin lymphoma survivors. Front. Oncol., 2022, Vol. 11, 790891. doi: 10.3389/fonc.2021.790891.

30. Zhong C., Gragert L., Maiers M., Hill B.T., Garcia-Gomez J., Gendzekhadze K., Senitzer D., Song J., Weisenburger D., Goldstein L., Wang S.S. The association between HLA and nonHodgkin lymphoma subtypes, among a transplant-indicated population. Leuk. Lymphoma, 2019, Vol. 60, no. 12, pp. 2899-2908.