EXPRESSION PROFILE OF SOME MARKERS OF LEUKEMIC STEM CELLS IN ACUTE MYELOID LEUKEMIA

L.M. Shlapatska, A.S. Polishchuk, D.F. Gluzman
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of NAS of Ukraine, Kyiv, Ukraine

DOI: https://doi.org/10.15407/oncology.2023.03.180

Summary. Aim: identification of a potential pool of leukemic stem cells based on the combined expression of CD34, CD38 and CD117 in different acute myeloid leukemia (AML) subtypes. Object and methods: the studies were conducted on samples of bone marrow aspirates from 54 patients with newly diagnosed and untreated AML. The profile of the expression of surface antigens on leukemic (blast) cells of AML patients was studied by flow cytometry. Results: differences were found in the number of CD34+CD38–, CD34+CD38+, CD34–CD117+ and CD34+CD117+ cells, which can be leukemic stem cells (LSCs), among patients with different AML subtypes. The median percentage of CD34+CD38– cells in M2 AML (3.9%) and M3 AML (2.5%) is significantly lower than in M1 AML (11.3%) and M5 AML (13.0%), while the content of CD34+CD38+ cells is most represented in M2 AML and M5 AML. The analysis of the combined expression of CD34 and CD117 shows that M3 AML is more characterized by the presence of a population of CD34–CD117+ cells, while M1 AML and M5 AML are characterized by CD34+CD117+ blasts. Conclusion: in all studied AML subtypes, compartments of malignantly transformed cells, that potentially may be LSCs have been identified and are determined by the combined expression of CD34, CD38 and CD117. These studies are promising, since the definition of LSCs is the foundation for effective targeted therapy in patients with AML.

References

1. Plesa A, Dumontet C, Mattei E, et al. High frequency of CD34+CD38-/low immature leukemia cells is correlated with unfavorable prognosis in acute myeloid leukemia. World J Stem Cells 2017; 9 (12): 227–34. doi: 10.4252/wjsc.v9.i12.227.
2. Bill M, Nicolet D, Kohlschmidt J, et al. Mutations associated with a 17-gene leukemia stem cell score and the score’s prognostic relevance in the context of the European LeukemiaNet classification of acute myeloid leukemia. Haematologica 2020; 105 (3): 721–9. doi: 10.3324/haematol.2019.225003.
3. Goardon N, Marchi E, Atzberger A, et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 2011; 19 (1): 138–52. doi: 10.1016/j.ccr.2010.12.012.
4. Sarry J, Murphy K, Perry R, et al. Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice. J Clin Invest 2011; 121 (1): 384–95. doi: 10.1172/JCI41495.
5. Quek L, Otto G, Garnett C, et al. Genetically distinct leukemic stem cells in human CD34− acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. J Exp Med 2016; 213 (8): 1513–35. doi/10.1084/jem.20151775.
6. Jiang L, Li XP, Dai YT, et al. Multidimensional study of the heterogeneity of leukemia cells in t(8;21) acute myelogenous leukemia identifies the subtype with poor outcome. Proc Natl Acad Sci USA 2020; 117 (33): 20117– doi: 10.1073/pnas.2003900117.
7. Wood BL, Arroz M, Barnett JM, et al. 2006 Bethesda International Consensus recommendations on the immunophenotypic analysis of hematolymphoid neoplasia by flow cytometry: optimal reagents and reporting for the flow cytometric diagnosis of hematopoietic neoplasia. Cytometry B Clin Cytom 2007; 72 (1): 14– doi: 10.1002/cyto.b.20363.
8. van Dongen JJ, Orfao A. EuroFlow Consortium. EuroFlow: Resetting leukemia and lymphoma immunophenotyping. Basis for companion diagnostics and personalized medicine. Leukemia 2012; 26 (9): 1899– doi: 10.1038/leu.2012.121.
9. Shlapatska L, Gordiienko I, Polishchuk A, Gluzman D. Profile of CD150 expression in bone marrow cells of patients with acute myeloid leukemia. Exp Oncol 2022; 44 (3): 198–207. doi: 10.32471/exp-oncology.2312-8852.vol-44-no-3.18307.
10. Selleri C, Notaro R, Catalano L, et al. Prognostic irrelevance of CD34 in acute myeloid leukaemia. Br J Haematol 1992; 82 (2): 479–81. doi: 10.1111/j.1365-2141.1992.tb06452.x.
11. Noguera NI, Catalano G, Banella C, et al. Acute promyelocytic leukemia: update on the mechanisms of leukemogenesis, resistance and on innovative treatment strategies. Сancers (Basel) 2019; 11 (10): 1591. doi: 10.3390/cancers11101591.
12. Ashman LK, Cambareri AC, To LB, et al. Expression of the YB5.B antigen (c‐kit proto‐oncogene product) in normal human bone marrow. Blood 1991; 78 (1): 30–7. doi: 10.1182/blood.V78.1.30.bloodjournal78130.
13. van Lochem EG, van der Velden VH, Wind HK, et al. Immunophenotypic differentiation patterns of normal hematopoiesis in human bone marrow: reference patterns for age‐related changes and disease‐induced shifts. Cytometry 2004; 60 (1): 1–13. doi: 10.1002/cyto.b.20008.
14. Woźniak J, Kopeć-Szlezak J. c-Kit receptor (CD117) expression on myeloblasts and white blood cell counts in acute myeloid leukemia. Cytometry B Clin Cytom 2004; 58 (1): 9– doi: 10.1002/cyto.b.10068.
15. Goryainova NV, Gordienko AI, Kubarova VA. CD117 expression on blast cells in acute myeloid leukemia. Medicni perspektivi 2015; ХХ (3): 73–9. http://nbuv.gov.ua/UJRN/Mp_2015_20_3_15.
16. Bhat S, Rahim F, Geelani S, et al. CD 117: Lineage assigning marker in acute myeloid leukemias. Int J Adv Med 2019; 6 (2): 382–8. doi:18203/2349-3933.ijam20191145.
17. Cascavilla N, Musto P, D’Arena G, et al. CD117 (c-kit) is a restricted antigen of acute myeloid leukemia and characterizes early differentiative levels of M5 FAB subtype. Haematologica 1998; 83 (5): 392–7. PMID: 9658721.
18. Zahran AM, Aly SS, Rayan A, et al. Survival outcomes of CD34+CD38- LSCs and their expression of CD123 in adult AML patients. Oncotarget 2018; 9 (75): 34056–65. doi: 10.18632/oncotarget.26118.
19. Zeijlemaker W, Grob T, Meijer R, et al. CD34+CD38– leukemic stem cell frequency to predict outcome in acute myeloid leukemia. Leukemia 2019; 33 (5): 1102–12. doi: 10.1038/s41375-018-0326-3.
20. Terwijn M, Zeijlemaker W, Kelder A, et al. Leukemic stem cell frequency: a strong biomarker for clinical outcome in acute myeloid leukemia. PLoS One 2014; 9 (9): e107587. doi: 10.1371/journal.pone.0107587.
21. El-Meligui YM, Abd Elrhman HE, Salahuddin A, et al. Correlation study on HLA-DR and CD117 (c-kit) expressions: its prognosis and treatment response in acute myeloid leukemia patients. Pharmgenomics Pers Med 2021; 14: 381– doi: 10.2147/PGPM.S268986.
22. Li X, Dai Y, Chen B, et al. Clinical signifcance of CD34(+)CD117(dim)/CD34(+)CD117(bri) myeloblast‑associated gene expression in t(8;21) acute myeloid leukemia. Front Med 2021; 15 (4): 608–20. doi: 10.1007/s11684-021-0836-7.
23. Subirá D, Alhan C, Porwit A, et al. Monitoring treatment with 5-azacitidine by f low cytometry predicts duration of hematological response in patients with myelo-dysplastic syndrome. Ann Hematol 2021; 100 (7): 1711–2. doi: 10.1007/s00277-021-04411-4.
24. Brouwer N, Matarraz S, Nierkens S, et al. Immunophenotypic analysis of acute megakaryoblastic leukemia: a euroflow study. Cancers (Basel) 2022; 14 (6): doi: 10.3390/cancers14061583.
25. Uçkan D, Hiçsönmez G, Yetgin S, et al. CD34/CD117 co-expression in childhood acute leukemia. Leuk Res 2000; 24 (3): 201– doi: 10.1016/s0145-2126(99)00183-6.
26. van Rhenen A, Moshaver B, Kelder A, et al. Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia 2007; 21 (8): 1700–07. doi: 1038/sj.leu.2404754.