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Open Access 01-12-2024 | Myelodysplastic Syndrome | Research

Sequential gene expression analysis of myelodysplastic syndrome transformation identifies HOXB3 and HOXB7 as the novel targets for mesenchymal cells in disease

Authors: Chunlai Yin, Yanqi Li, Cheng Zhang, Shizhu Zang, Zilong Wang, Xue Yan, Tonghui Ma, Xia Li, Weiping Li

Published in: BMC Cancer | Issue 1/2024

Abstract

Background

Myelodysplastic syndrome (MDS) is known to arise through the pathogenic bone marrow mesenchymal stem cells (MSC) by interacting with hematopoietic stem cells (HSC). However, due to the strong heterogeneity of MDS patients, it is difficult to find common targets in studies with limited sample sizes. This study aimed to describe sequential molecular changes and identify biomarkers in MSC of MDS transformation.

Methods

Multidimensional data from three publicly available microarray and TCGA datasets were analyzed. MDS-MSC was further isolated and cultured in vitro to determine the potential diagnostic and prognostic value of the identified biomarkers.

Results

We demonstrated that normal MSCs presented greater molecular homogeneity than MDS-MSC. Biological process (embryonic skeletal system morphogenesis and angiogenesis) and pathways (p53 and MAPK) were enriched according to the differential gene expression. Furthermore, we identified HOXB3 and HOXB7 as potential causative genes gradually upregulated during the normal-MDS-AML transition. Blocking the HOXB3 and HOXB7 in MSCs could enhance the cell proliferation and differentiation, inhibit cell apoptosis and restore the function that supports hematopoietic differentiation in HSCs.

Conclusion

Our comprehensive study of gene expression profiling has identified dysregulated genes and biological processes in MSCs during MDS. HOXB3 and HOXB7 are proposed as novel surrogate targets for therapeutic and diagnostic applications in MDS.

Alvarez-Larran A, Lopez-Guerra M, Rozman M, Correa JG, Hernandez-Boluda JC, Tormo M, Martinez D, Martin I, Colomer D, Esteve J, et al. Genomic characterization in triple-negative primary myelofibrosis and other myeloid neoplasms with bone marrow fibrosis. Ann Hematol. 2019;98(10):2319–28.CrossRefPubMed

Chang YH. Myelodysplastic syndromes and overlap syndromes. Blood Res. 2021;56(S1):51–S64.CrossRefPubMedCentral

Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, Grauman PV, Hu ZH, Spellman SR, Lee SJ, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376(6):536–47.CrossRefPubMedPubMedCentral

Platzbecker U, Kubasch AS, Homer-Bouthiette C, Prebet T. Current challenges and unmet medical needs in myelodysplastic syndromes. Leukemia. 2021;35(8):2182–98.CrossRefPubMedPubMedCentral

Veryaskina YA, Titov SE, Kovynev IB, Fedorova SS, Pospelova TI, Zhimulev IF. MicroRNAs in the Myelodysplastic Syndrome. Acta Naturae. 2021;13(2):4–15.CrossRefPubMedPubMedCentral

Platzbecker U. Treatment of MDS. Blood. 2019;133(10):1096–107.CrossRefPubMed

Gupta VA, Matulis SM, Conage-Pough JE, Nooka AK, Kaufman JL, Lonial S, Boise LH. Bone marrow microenvironment-derived signals induce Mcl-1 dependence in multiple myeloma. Blood. 2017;129(14):1969–79.CrossRefPubMedPubMedCentral

Uder C, Bruckner S, Winkler S, Tautenhahn HM, Christ B. Mammalian MSC from selected species: features and applications. Cytometry A. 2018;93(1):32–49.CrossRefPubMed

Schroeder T, Geyh S, Germing U, Haas R. Mesenchymal stromal cells in myeloid malignancies. Blood Res. 2016;51(4):225–32.CrossRefPubMedPubMedCentral

10.

Jiang B, Yao G, Tang X, Yang X, Feng X. MSCs relieve SLE by modulation of Th17 cells through MMPs–CCL2–CCR2–IL-17 pathway. 2021, 1(1):30–9.

11.

Huang JC, Basu SK, Zhao X, Chien S, Fang M, Oehler VG, Appelbaum FR, Becker PS. Mesenchymal stromal cells derived from acute myeloid leukemia bone marrow exhibit aberrant cytogenetics and cytokine elaboration. Blood Cancer J. 2015;5:e302.CrossRefPubMedPubMedCentral

12.

Rathnayake AJ, Goonasekera HW, Dissanayake VH. Phenotypic and Cytogenetic Characterization of Mesenchymal Stromal Cells in De Novo Myelodysplastic Syndromes. Anal Cell Pathol (Amst) 2016, 2016:8012716.

13.

Abbas S, Kumar S, Srivastava VM, Therese MM, Nair SC, Abraham A, Mathews V, George B, Srivastava A. Heterogeneity of mesenchymal stromal cells in Myelodysplastic Syndrome-with Multilineage Dysplasia (MDS-MLD). Indian J Hematol Blood Transfus. 2019;35(2):223–32.CrossRefPubMedPubMedCentral

14.

Corradi G, Baldazzi C, Ocadlikova D, Marconi G, Parisi S, Testoni N, Finelli C, Cavo M, Curti A, Ciciarello M. 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 Res Ther. 2018;9(1):271.CrossRefPubMedPubMedCentral

15.

Sarhan D, Wang J, Sunil Arvindam U, Hallstrom C, Verneris MR, Grzywacz B, Warlick E, Blazar BR, Miller JS. Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function. JCI Insight 2020, 5(5).

16.

Kim M, Hwang S, Park K, Kim SY, Lee YK, Lee DS. Increased expression of interferon signaling genes in the bone marrow microenvironment of myelodysplastic syndromes. PLoS ONE. 2015;10(3):e0120602.CrossRefPubMedPubMedCentral

17.

Geyh S, Rodriguez-Paredes M, Jager P, Koch A, Bormann F, Gutekunst J, Zilkens C, Germing U, Kobbe G, Lyko F, et al. Transforming growth factor beta1-mediated functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2018;103(9):1462–71.CrossRefPubMedPubMedCentral

18.

Chen W, Yu Y, Zheng SG, Lin J. Human gingival tissue-derived mesenchymal stem cells inhibit proliferation and invasion of rheumatoid fibroblast-like synoviocytes via the CD39/CD73 signaling pathway. 2023, 3(2):90–9.

19.

Zhao ZG, Xu W, Yu HP, Fang BL, Wu SH, Li F, Li WM, Li QB, Chen ZC, Zou P. Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes. Cancer Lett. 2012;317(2):136–43.CrossRefPubMed

20.

Miao R, Lim VY, Kothapalli N, Ma Y, Fossati J, Zehentmeier S, Sun R, Pereira JP. Hematopoietic stem cell niches and signals Controlling Immune Cell Development and maintenance of immunological memory. Front Immunol. 2020;11:600127.CrossRefPubMedPubMedCentral

21.

Poon Z, Dighe N, Venkatesan SS, Cheung AMS, Fan X, Bari S, Hota M, Ghosh S, Hwang WYK. Bone marrow MSCs in MDS: contribution towards dysfunctional hematopoiesis and potential targets for disease response to hypomethylating therapy. Leukemia. 2019;33(6):1487–500.CrossRefPubMed

22.

Hosono N. Genetic abnormalities and pathophysiology of MDS. Int J Clin Oncol. 2019;24(8):885–92.CrossRefPubMed

23.

Scalzulli E, Pepe S, Colafigli G, Breccia M. Therapeutic strategies in low and high-risk MDS: what does the future have to offer? Blood Rev. 2021;45:100689.CrossRefPubMed

24.

Pang YB, Li WW, Luo JM, Ji J, Du X. [Senescent mesenchymal stem cells contribute to progression of myelodysplastic Syndromes-Review]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018;26(3):942–6.PubMed

25.

Wei Y, Huang YH, Skopelitis DS, Iyer SV, Costa ASH, Yang Z, Kramer M, Adelman ER, Klingbeil O, Demerdash OE, et al. SLC5A3-Dependent Myo-Inositol Auxotrophy in Acute myeloid leukemia. Cancer Discov. 2022;12(2):450–67.CrossRefPubMed

26.

Tejeda-Mora H, Leon LG, Demmers J, Baan CC, Reinders MEJ, Bleck B, Lombardo E, Merino A, Hoogduijn MJ. Proteomic analysis of mesenchymal stromal cell-derived extracellular vesicles and reconstructed membrane particles. Int J Mol Sci 2021, 22(23).

27.

Geyh S, Oz S, Cadeddu RP, Frobel J, Bruckner B, Kundgen A, Fenk R, Bruns I, Zilkens C, Hermsen D, et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia. 2013;27(9):1841–51.CrossRefPubMed

28.

Inamura N, Araki T, Enokido Y, Nishio C, Aizawa S, Hatanaka H. Role of p53 in DNA strand break-induced apoptosis in organotypic slice culture from the mouse cerebellum. J Neurosci Res. 2000;60(4):450–7.CrossRefPubMed

29.

Chen SX, Zhao F, Huang XJ. [MAPK signaling pathway and erectile dysfunction]. Zhonghua Nan Ke Xue. 2018;24(5):442–6.PubMed

30.

Calkoen FG, Vervat C, van Pel M, de Haas V, Vijfhuizen LS, Eising E, Kroes WG, t Hoen PA, van den Heuvel-Eibrink MM, Egeler RM, et al. Despite differential gene expression profiles pediatric MDS derived mesenchymal stromal cells display functionality in vitro. Stem Cell Res. 2015;14(2):198–210.CrossRefPubMed

31.

Zhu L, Yu S, Jiang S, Ge G, Yan Y, Zhou Y, Niu L, He J, Ren Y, Wang B. Loss of HOXB3 correlates with the development of hormone receptor negative breast cancer. PeerJ. 2020;8:e10421.CrossRefPubMedPubMedCentral

32.

Mallo M. Reassessing the role of hox genes during Vertebrate Development and Evolution. Trends Genet. 2018;34(3):209–17.CrossRefPubMed

33.

Lindblad O, Chougule RA, Moharram SA, Kabir NN, Sun J, Kazi JU, Ronnstrand L. The role of HOXB2 and HOXB3 in acute myeloid leukemia. Biochem Biophys Res Commun. 2015;467(4):742–7.CrossRefPubMed

34.

Bi L, Zhou B, Li H, He L, Wang C, Wang Z, Zhu L, Chen M, Gao S. A novel miR-375-HOXB3-CDCA3/DNMT3B regulatory circuitry contributes to leukemogenesis in acute myeloid leukemia. BMC Cancer. 2018;18(1):182.CrossRefPubMedPubMedCentral

35.

Zhang J, Zhang S, Li X, Zhang F, Zhao L. HOXB5 promotes the progression of breast cancer through wnt/beta-catenin pathway. Pathol Res Pract. 2021;224:153117.CrossRefPubMed

36.

Sakamaki T, Kao KS, Nishi K, Chen JY, Sadaoka K, Fujii M, Takaori-Kondo A, Weissman IL, Miyanishi M. Hoxb5 defines the heterogeneity of self-renewal capacity in the hematopoietic stem cell compartment. Biochem Biophys Res Commun. 2021;539:34–41.CrossRefPubMed

37.

Chen M, Qu Y, Yue P, Yan X. The prognostic value and function of HOXB5 in Acute myeloid leukemia. Front Genet. 2021;12:678368.CrossRefPubMedPubMedCentral

38.

Giampaolo A, Felli N, Diverio D, Morsilli O, Samoggia P, Breccia M, Lo Coco F, Peschle C, Testa U. Expression pattern of HOXB6 homeobox gene in myelomonocytic differentiation and acute myeloid leukemia. Leukemia. 2002;16(7):1293–301.CrossRefPubMed

39.

Fischbach NA, Rozenfeld S, Shen W, Fong S, Chrobak D, Ginzinger D, Kogan SC, Radhakrishnan A, Le Beau MM, Largman C, et al. HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo. Blood. 2005;105(4):1456–66.CrossRefPubMed

40.

Dai L, Hu W, Yang Z, Chen D, He B, Chen Y, Zhou L, Xie H, Wu J, Zheng S. Upregulated expression of HOXB7 in intrahepatic cholangiocarcinoma is associated with tumor cell metastasis and poor prognosis. Lab Invest. 2019;99(6):736–48.CrossRefPubMedPubMedCentral

41.

Jann JC, Mossner M, Riabov V, Altrock E, Schmitt N, Flach J, Xu Q, Nowak V, Oblander J, Palme I, et al. Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo. Nat Commun. 2021;12(1):6170.CrossRefPubMedPubMedCentral

Title: Sequential gene expression analysis of myelodysplastic syndrome transformation identifies HOXB3 and HOXB7 as the novel targets for mesenchymal cells in disease
Authors: Chunlai Yin
Yanqi Li
Cheng Zhang
Shizhu Zang
Zilong Wang
Xue Yan
Tonghui Ma
Xia Li
Weiping Li
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Myelodysplastic Syndrome
Published in: BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-024-11859-w

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