Abstract
The presence of cytogenetic aberrations on mesenchymal stem cells (MSC) from myelodysplastic syndrome (MDS) patients is controversial. The aim of the study is to characterize bone marrow (BM) derived MSC from patients with MDS using: kinetic studies, immunophenotyping, fluorescent in situ hybridization (FISH) and genetic changes by array-based comparative genomic hybridization (array-CGH). In all 36 cases of untreated MDS were studied. MDS–MSC achieved confluence at a significantly slower rate than donor-MSC, and the antigenic expression of CD105 and CD104 was lower. Array-CGH studies showed DNA genomic changes that were proved not to be somatic. These results were confirmed by FISH. To confirm that genomic changes were also present in freshly obtained MSCs they were enriched by sorting BM cells with the following phenotype: CD45−/CD73++/CD34−/CD271++. They also showed genomic changes that were confirmed by FISH. To analyze the relationship of these aberrations with clinical–biological data an unsupervized hierarchical cluster analysis was performed, two clusters were identified: the first one included the 5q− syndrome patients, whereas the other incorporated other MDS. Our results show, for the first time that MSC from MDS display genomic aberrations, assessed by array-CGH and FISH, some of them specially linked to a particular MDS subtype, the 5q− syndrome.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Catenacci DV, Schiller GJ . Myelodysplasic syndromes: a comprehensive review. Blood Rev 2005; 19: 301–319.
List AF, Vardiman J, Issa JP, DeWitte TM . Myelodysplastic syndromes. Hematol Am Soc Hematol Educ Program 2004, 297–317.
Fenaux P . Myelodysplastic syndromes: From pathogenesis and prognosis to treatment. Semin Hematol 2004; 41: 6–12.
Tauro S, Hepburn MD, Bowen DT, Pippard MJ . Assessment of stromal function, and its potential contribution to deregulation of hematopoiesis in the myelodysplastic syndromes. Haematologica 2001; 86: 1038–1045.
Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, rana-Trejo RM, Mayani H . In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res 2002; 26: 677–686.
Deeg HJ . Marrow stroma in MDS: culprit or bystander? Leuk Res 2002; 26: 687–688.
Soenen-Cornu V, Tourino C, Bonnet ML, Guillier M, Flamant S, Kotb R et al. Mesenchymal cells generated from patients with myelodysplastic syndromes are devoid of chromosomal clonal markers and support short- and long-term hematopoiesis in vitro. Oncogene 2005; 24: 2441–2448.
Flores-Figueroa E, rana-Trejo RM, Gutierrez-Espindola G, Perez-Cabrera A, Mayani H . Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization. Leuk Res 2005; 29: 215–224.
Blau O, Hofmann WK, Baldus CD, Thiel G, Serbent V, Schumann E et al. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp Hematol 2007; 35: 221–229.
Campioni D, Moretti S, Ferrari L, Punturieri M, Castodi GL, Lanza F . Immunophenotypic heterogeneity of bone marrow-derived mesenchymal stromal cells from patients with hematologic disorders: correlation with bone marrow microenvironment. Haematologica 2006; 91: 364–368.
Ramakrishnan A, Awaya N, Bryant E, Torok-Storb B . The stromal component of the marrow microenvironment is not derived from the malignant clone in MDS. Blood 2006; 108: 772–773.
Vardiman JW, Harris NL, Brunning RD . The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100: 2292–2302.
Minguell JJ, Erices A, Conget P . Mesenchymal stem cells. Exp Biol Med (Maywood) 2001; 226: 507–520.
Villaron EM, Almeida J, Lopez-Holgado N, Alcoceba M, Sanchez-Abarca LI, Sanchez-Guijo FM et al. Mesenchymal stem cells are present in peripheral blood and can engraft after allogeneic hematopoietic stem cell transplantation. Haematologica 2004; 89: 1421–1427.
Dominici M, Le Blanc K, Mueller I, Slapar-Cortenbach I, Marini F, Krause D et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–317.
del Canizo MC, Fernandez ME, Lopez A, Vidriales B, Villaron E, Arroyo JL et al. Immunophenotypic analysis of myelodysplastic syndromes. Haematologica 2003; 88: 402–407.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.
Conget PA, Minguell JJ . Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. J Cell Physiol 1999; 181: 67–73.
Blanco B, Perez-Simon JA, Sanchez-Abarca LI, Carvajal-Vergara X, Mateos J, Vidriales B et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood 2006; 107: 3575–3583.
Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 2006; 108: 2366–2372.
Buhring HJ, Battula VL, Treml S, Schewe B, Kanz L, Vogel W . Novel markers for the prospective isolation of human MSC. Ann N Y Acad Sci 2007; 1106: 262–271.
Carter NP, Fiegler H, Piper J . Comparative analysis of comparative genomic hybridization microarray technologies: report of a workshop sponsored by the Wellcome Trust. Cytometry 2002; 49: 43–48.
Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Scott CE et al. DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 2003; 36: 361–374.
Herrero J, Al-Shahrour F, az-Uriarte R, Mateos A, Vaquerizas JM, Santoyo J et al. GEPAS: A web-based resource for microarray gene expression data analysis. Nucleic Acids Res 2003; 31: 3461–3467.
Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95: 14863–14868.
Tusher VG, Tibshirani R, Chu G . Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001; 98: 5116–5121.
Gonzalez MB, Hernandez JM, Garcia JL, Lumbreras E, Castellanos M, Hernandez JM et al. The value of fluorescence in situ hybridization for the detection of 11q in multiple myeloma. Haematologica 2004; 89: 1213–1218.
Perez-Simon JA, Caballero D, Diez-Campelo M, Lopez-Pérez R, Mateos G, Canizo C et al. Chimerism and minimal residual disease monitoring after reduced intensity conditioning (RIC) allogeneic transplantation. Leukemia 2002; 16: 1423–1431.
Li H, Fan X, Houghton J . Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem 2007; 101: 805–815.
Hellstrom-Lindberg E, Willman C, Barrett AJ, Saunthararajah Y . Achievements in understanding and treatment of myelodysplastic syndromes. Hematol Am Soc Hematol Educ Program 2000, 110–132.
Mufti GJ . Pathobiology, classification, and diagnosis of myelodysplastic syndrome. Best Pract Res Clin Haematol 2004; 17: 543–557.
Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 2008; 451: 335–339.
List AF . New approaches to the treatment of myelodysplasia. Oncologist 2002; 7 (Suppl 1): 39–49.
Corey SJ, Minden MD, Barber DL, Kantarjian H, Wang JC, Schimmer AD . Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer 2007; 7: 118–129.
Cazzola M . Myelodysplastic syndrome with isolated 5q deletion (5q- syndrome). A clonal stem cell disorder characterized by defective ribosome biogenesis. Haematologica 2008; 93: 967–972.
Albini A, Sporn MB . The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 2007; 7: 139–147.
Ishiguro K, Yoshida T, Yagishita H, Numata Y, Okayasu T . Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas. Gut 2006; 55: 695–702.
Mueller MM, Fusenig NE . Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 2004; 4: 839–849.
Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC . Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007; 7: 585–598.
Giagounidis AA, Haase S, Heinsch M, Gohring G, Schlegelberg B, Aul C . Lenalidomide in the context of complex karyotype or interrupted treatment: case reviews of del(5q)MDS patients with unexpected responses. Ann Hematol 2007; 86: 133–137.
Mufti G, List AF, Gore SD, Ho AY . Myelodysplastic syndrome. Hematol Am Soc Hematol Educ Program 2003, 176–199.
Acknowledgements
We thank Dr JG Briñon for his assistance with the chondrocytic staining; Dr J Almeida for her assistance with the immunophenotypic studies and Irene Rodriguez and Sara González for their assistance with the array-CGH studies. This work was partially supported by JCyL Grants JA10 (Estudio de las células stem mesenquimales en los síndromes mielodisplásicos, interacción con los progenitors hematopoyéticos 2005–2006) and HUS02A07 (Células stem mesenquimales en los síndromes mielodisplásicos: papel en la patogenia de la enfermedad 2007–2009).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
Supplementary information
Rights and permissions
About this article
Cite this article
Lopez-Villar, O., Garcia, J., Sanchez-Guijo, F. et al. Both expanded and uncultured mesenchymal stem cells from MDS patients are genomically abnormal, showing a specific genetic profile for the 5q− syndrome. Leukemia 23, 664–672 (2009). https://doi.org/10.1038/leu.2008.361
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2008.361
Keywords
This article is cited by
-
Mesenchymal stromal cell senescence in haematological malignancies
Cancer and Metastasis Reviews (2023)
-
Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo
Nature Communications (2021)
-
Heterogeneity of Mesenchymal Stromal Cells in Myelodysplastic Syndrome-with Multilineage Dysplasia (MDS-MLD)
Indian Journal of Hematology and Blood Transfusion (2019)
-
Mesenchymal stromal cells from myelodysplastic and acute myeloid leukemia patients display in vitro reduced proliferative potential and similar capacity to support leukemia cell survival
Stem Cell Research & Therapy (2018)
-
Role of the microenvironment in myeloid malignancies
Cellular and Molecular Life Sciences (2018)