TSitologiya i Genetika 2022, vol. 56, no. 5, 32-40
Cytology and Genetics 2022, vol. 56, no. 5, 423–430, doi: https://www.doi.org/10.3103/S0095452722050024

Comparative characteristics of cytogenetic anomalies in different types of myelodysplastic syndromes

Andreieva S.V., Korets K., Skorohod I., Starodub H.

SUMMARY. Comparison of cytogenetic and molecular-cytogenetic rearrangements of bone marrow cells in 251 patients at diagnosis of myelodysplastic syndromes (MDS) and in 7 - in the transformation into secondary acute myeloid leukemia was carry out. Significant heterogeneity of karyotypes in the structure of clones in all isolated forms of MDS and in transformed MDS into secondary acute myeloid leukemias was established and indicating a different genetic composition of bone marrow cells. It is shown that the evolution of clonal chromosome abnormalities is a universal mechanism for the formation of abnormal clones. An increase in the frequency of pseudodiploid and hypodiploid clones depending on the complexity of the form of MDS were marked: pseudodiploid from 4.5 % in MDS with single-line dysplasia (RA) to 27.3 % in MDS with excess blasts (RAEB 1–2), hypodiploid – from 4.5 in RA to 18.2 at RAEB 1–2)were shown, which is associated with the loss of genetic material. In the group of RA losses of genetic material in the form of deletions (57.9 %) more often recorded. Chromosome 11 (31.6 %) was more often involved in structural rearrangements.

Keywords: myelodysplastic syndromes, bone marrow, chromosome abnormalities

TSitologiya i Genetika
2022, vol. 56, no. 5, 32-40

Current Issue
Cytology and Genetics
2022, vol. 56, no. 5, 423–430,
doi: 10.3103/S0095452722050024

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Bieganowski, P., Garrison, P.N., Hodawadekar, S.C., Faye, G., Barnes, L.D., and Brenner, Ch., Show footnotes adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1, and Tfb3, Mech. Signal Transduction, 2002, vol. 277, no. 13, pp. 10852–10860.

Boaretto, F., Cacciavillani, M., Mostacciuolo, M.L., Spalletta, A., Piscosquito, G., Pareyson, D., Vazza, G., and Briani, C., Novel loss-of-function pathogenic variant of the HINT1 gene in a patient with distal motor axonal neuropathy without neuromyotonia, Muscle Nerve, 2015, vol. 52, no. 4, pp. 688–689. https://doi.org/10.1002/mus.24720

Braga, B., Gomes, N., Nishi, M., Freire, B., et al., Variants in 46, XY DSDRelated genes in syndromic and non-syndromic small for gestational age children with hypospadias, Sex. Dev., 2022, vol. 16, no. 1, pp. 27–33. https://doi.org/10.1159/000518091

Brenner, Ch., Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases, Biochemistry, 2002, vol. 41, no. 29, pp. 9003–9014. https://doi.org/10.1021/bi025942q

Chou, T.F. and Wagner, C.R., Lysyl-tRNA synthetase-generated lysyl-adenylate is a substrate for histidine triad nucleotide binding proteins, J. Biol. Chem., 2007, vol. 282, no. 7, pp. 4719–4727. https://doi.org/10.1074/jbc.M610530200

Chou, T.F., Tikh, I.B., Horta, B.A., et al., Engineered monomeric human histidine triad nucleotide-binding protein 1 hydrolyzes fluorogenic acyl-adenylate and lysyl-tRNA synthetase-generated lysyl-adenylate, J. Biol. Chem., 2007, vol. 282, no. 20, pp. 15137–15147.

Eggers, S., Ohnesorg, T., and Sinclair, A., Genetic regulation of mammalian gonad development, Nat. Rev. Endocrinol., 2014, vol. 10, pp. 673–683.

Ergun-Longmire, B., Vinci, G., Alonso, L., Matthew, S., Tansil, S., Lin-Su, K., McElreavey, K., and New, M.I., Clinical, hormonal and cytogenetic evaluation of 46, XX males and review of the literature, J. Pediatr. Endocrinol. Metab., 2005, vol. 18, no. 8, pp. 739–748. https://doi.org/10.1515/jpem.2005.18.8.739

Estermann, M.A. and Smith, C.A., Applying single-cell analysis to gonadogenesis and DSDs (Disorders/Differences of Sex Development), Int. J. Mol. Sci., 2020, vol. 21, no. 18, art. ID 6614.

Ilaslan, E., Markosyan, R., Sproll, P., Stevenson, B.J., Sajek, M., Sajek, M.P., Hayrapetyan, H., Sarkisian, T., Livshits, L., Nef, S., Jaruzelska, J., and Kusz-Zamelczyk, K., The FKBP4 gene, encoding a regulator of the androgen receptor signaling pathway, is a novel candidate gene for androgen insensitivity syndrome, Int. J. Mol. Sci., 2020, vol. 21, no. 21, art. ID 8403. https://doi.org/10.3390/ijms21218403

Lamothe, S., Bernard, V., and Christin-Maitre, S., Gonad differentiation toward ovary, Ann. d’Endocrinol., 2020, vol. 81, nos. 2–3, pp. 83–88.

Laššuthová, P., Brožková, D.Š., Krůtová, M., Neupauerová, J., Haberlová, J., Mazanec, R., Dvořáčková, N., Goldenberg, Z., and Seeman, P., Pathogenic variants in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom, Neurogenetics, 2015, vol. 16, no. 1, pp. 43–54. https://doi.org/10.1007/s10048-014-0427-8

Madeiro, B. de A.C.S., Peeters, K., Santos de Lima, E.L., Amor-Barris, S., Els, De Vriendt, Jordanova, A., Cartaxo Muniz, M.T., da Cunha Correia, C., HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report, Mol. Genet. Genomic Med., 2021, vol. 9, no. 10, art. ID e1783.https://doi.org/10.1002/mgg3.1783

Majzoub, A., Arafa, M., Starks, Ch., Elbardisi, H., Said, S.Al., and Sabanegh, E., 46,XX karyotype during male fertility evaluation; case series and literature review, Asian J. Androl., 2017, vol. 19, no. 2, pp. 168–172.

Martínez de LaPiscina, I., Mahmoud, R.A., Sauter, K.-S., Esteva, I., Alonso, M., Costa, I., Rial-Rodriguez, J.M., Rodríguez-Estévez, A., Vela, A., Castano, L., and Flück, C.E., Variants of STAR, AMH and ZFPM2/ FOG2 may contribute towards the broad phenotype observed in 46,XY DSD patients with heterozygous variants of NR5A1, Int. J Mol Sci., 2020, vol. 21, no. 22, art. ID 8554.

Nøstvik, M., Kateta, S.M., Schönewolf-Greulich, B., Barth, A.A.M., Boschann, F., Doummar, D., Haack, T.B., Keren, B., Livshits, L.A., Mei, D., Park, J., Pisano, T., Prouteau, C., Umair, M., Waqas, A., Ziegler, A., Guerrini, R., Moller, R.S., and Tümer, Z., Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders, Clin. Genet., 2021, vol. 100, no. 5, pp. 628–633. https://doi.org/10.1111/cge.14051

Queralt, R., Madrigal, I., Vallecillos, M.A., Morales, C., Ballescá, J.-L., Oliva, R., Soler, A., Sánchez, A., and Margarit, E., Atypical XX male with the SRY gene located at the long arm of chromosome 1 and a 1qter microdeletion, Am. J. Med. Genet., 2008, vol. 146A, no. 10, pp. 1335–1340.

Rayevsky, A., Sirokha, D., Samofalova, D., Lozhko, D., Gorodna, O., Prokopenko, I., Livshits, L., Functional effects in silico prediction for androgen receptor ligand-binding domain novel I836S mutation, Life, 2021, vol. 11, no. 7, art. ID 659. https://doi.org/10.3390/life11070659

Shchagina, O.A., Milovidova, T.B., Murtazina, A.F., Rudenskaya, G.E., Nikitin, S.S., Dadali, E.L., and Polyakov, A.V., HINT1 gene pathogenic variants: the most common cause of recessive hereditary motor and sensory neuropathies in Russian patient, Mol. Biol. Rep., 2019, vol. 47, pp. 1331–1337. https://doi.org/10.1007/s11033-019-05238-z

Shu-Chin, Chien, Yueh-Chun, Li, Ming, Ho, Pei-Ching, Hsu, Ru-Hsiou, Teng, Wei-De, Lin, Fuu-Jen, Tsai, and Chyi-Chyang, Lin, Rare rearrangements: A “jumping satellite” in one family and autosomal location of the SRY gene in an XX male, Am. J. Med. Genet., 2009, vol. 149A, no. 12, art. ID 2775–2781.

Sirokha, D., Gorodna, O., Vitrenko, Y., Zelinska, N., Ploski, R., Nef, S., Jaruzelska, J., Kusz-Zamelczyk, K., and Livshits, L., A novel WT1 mutation identified in a 46,XX testicular/ovotesticular DSD patient results in the retention of intron 9, Biology, 2021, vol. 10, no. 12, art. ID 1248. https://doi.org/10.3390/biology10121248

Soloviov, O.O., Livshits, G.B., Podlesnaya, S.S., and Livshits, L.A., Implementation of the quantitative Real-Time PCR for the molecular-genetic diagnostics of spinal muscular atrophy, Biopolym. Cell, 2010, vol. 26, no. 1, pp. 51–55.

Weiske, J. and Huber, O., The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF–β-catenin-mediated transcription, J. Cell Sci., 2005, vol. 118, no. 14, pp. 3117–3129. https://doi.org/10.1242/jcs.02437

Zhao, H., Race, V., Matthijs, G., De Jonghe, P., Robberecht, W., Lambrechts, D., and Van Damme, P., Exome sequencing reveals HINT1 pathogenic variants as a cause of distal hereditary motor neuropathy, Eur. J. Hum. Genet., 2014, vol. 22, no. 6, pp. 847–850. https://doi.org/10.1038/ejhg.2013.231

Zimoń, M., Baets, J., Almeida-Souza, L., et al., Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia, Nat. Genet., 2012, vol. 44, no. 10, pp. 1080–1083. https://doi.org/10.1038/ng.2406

Arber, D.A., Orazi, A., Hasserjian, R., et al., The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, Blood, 2016, vol. 127, no. 20, pp. 2391–2405. https://doi.org/10.1182/blood-2016-03-643544

Avada, H., Thapa, B., and Visconte, V., The genomics of myelodysplastic Syndromes: origins of disease evolution, biological pathways, and prognostic implications, Cells, 2020, vol. 9, no. 11, art. ID 2512. https://doi.org/10.3390/cells9112512

Bacher, U., Haferlach, T., Schnittger, S., et al., Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact, Br. J. Haematol., 2014, vol. 164, no. 6, pp. 822–833. https://doi.org/10.1111/bjh.12710

Gersen, St.L., The Principles of Clinical Cytogenetics, New York: Springer-Verlag, 2013.


Gluzman, D., Sklyrenko, L., Koval, S., et al., Modern Classification and Diagnosis of Myelodysplastic Syndromes. Scientific-and-Methodical Quide, Kyiv: INTERSERVIS, 2018.

Haase, D., Stevenson, K.E., Neuberg, D., et al., TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups, Leukemia, 2019, vol. 33, pp. 1747–1758. https://doi.org/10.1038/s41375-018-0351-2

Karger, A.G. and Basel Greenberg, P.L., Myelodysplastic Syndromes. NCCN Evidence Blocks, 2021. https://www.nccn. org/professionals/physician_gls/pdf/mds_blocks.pdf. Cited January 15, 2021.

Komrokji, R.S., Padron, E., Ebert, B.L., et al., Deletion 5q MDS: Molecular and therapeutic implications, Best Pract. Res., Clin. Haematol., 2013, vol. 26, no. 4, pp. 365–375. https://doi.org/10.1016/j.beha.2013.10.013

Kumar, M.S., Narla, A., Nonami, A., et al., Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q− syndrome, Blood, vol. 118, no. 17, pp. 4666–4673. 2011. https://doi.org/10.1182/blood-2010-12-324715

Kuzmanovic, T., Patel, B.J., Sanikommu, S.R., et al., Genomics of therapy-related myeloid neoplasms, Haematologica, 2020, vol. 105, no. 3, art. ID e98. https://doi.org/10.3324/haematol.2019.219352

Lindsley, R.C. and Ebert, B.L., Molecular pathophysiology of myelodysplastic syndromes, Ann. Rev. Pathol., 2013, vol. 8, pp. 21–47. https://doi.org/10.1146/annurev-pathol-011811-132436

McGowan-Jordan, J., An International System for Human Cytogenomic Nomenclature (2020), 2021.

Ogawa, S., Genetics of MDS, Blood, 2019, vol. 133, no. 10, pp. 1049–1059. https://doi.org/10.1182/blood-2018-10-844621

Pellagatti, A. and Boultwood, J., The molecular pathogenesis of the myelodysplastic syndromes, Eur. J. Haematol., 2015, vol. 95, no. 1, pp. 3–15. https://doi.org/10.1111/ejh.12515

Sashida, G., Harada, H., Matsui, H., et al., Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation, Nat. Commun., 2014, vol. 5, art. ID 4177. https://doi.org/10.1038/ncomms5177

Saumell, S., Florensa, L., Luño, E., et al., Prognostic value of trisomy 8 as a single anomaly and the influence of additional cytogenetic aberrations in primary myelodysplastic syndromes, Br. J. Haematol., 2012, vol. 159, no. 3, pp. 311–321. https://doi.org/10.1111/bjh.12035

Schanz, J., Tüchler, H., Solé, F., et al., New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge, J. Clin. Oncol., 2012, vol. 30, no. 8, pp. 820–929. https://doi.org/10.1200/JCO.2011.35.6394

Shiseki, M., Ishii, M., Okada, M., et al., Expression analysis of genes located within the common deleted region of del(20q) in patients with myelodysplastic syndromes, Leuk. Res., 2019, vol. 84, art. ID 106175. https://doi.org/10.1016/j.leukres.2019.106175

Stoddart, A., Fernald, A.A., Wang, J., et al., Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice, Blood, 2014, vol. 123, no. 7, pp. 1069–1078. https://doi.org/10.1182/blood-2013-07-517953

Svobodova, K., Zemanova, Z., Lhotska, H., et al., Copy number neutral loss of heterozygosity at 17p and homozygous mutations of TP53 are associated with complex chromosomal aberrations in patients newly diagnosed with myelodysplastic syndromes, Leuk. Res., 2016, vol. 42, no. 1, pp. 7–12. https://doi.org/10.1016/j.leukres.2016.01.009

Veryaskina, Y.A., Titov, S.E., Kovynev, I.B., et al., Prognostic markers of myelodysplastic syndromes, Medicina (Kaunas), 2020, vol. 56, no. 8, art. ID 376. https://doi.org/10.3390/medicina56080376

Xu, F., Liu, L., Chang, C.K., et al., Genomic loss of EZH2 leads to epigenetic modifications and overexpression of the HOX gene clusters in myelodysplastic syndrome, Oncotarget, 2016, vol. 7, no. 7, pp. 8119–8130. https://doi.org/10.18632/oncotarget.6992