Murine xenogeneic models of myelodysplastic syndrome: An essential role for stroma cells
2013; Elsevier BV; Volume: 42; Issue: 1 Linguagem: Inglês
10.1016/j.exphem.2013.10.002
ISSN1873-2399
Autores Tópico(s)Cancer Cells and Metastasis
ResumoThe objective of is this article is to review murine xenotransplantation models for myelodysplastic syndromes (MDS). The difficulties in achieving sustained engraftment of MDS cells in immunodeficient mice may lie in innate characteristics of the MDS clones and microenvironmental factors. Engraftment of very low numbers of CD45+ clonal MDS cells has been achieved with intravenous injection; higher rates of engraftment are obtained via the intramedullary route. Coinjection of certain stroma components with hematopoietic cells overcomes limitations of intravenous (IV) administration, allowing for engraftment of high proportions of human CD45+ cells in mouse spleen and marrow. Expression of CD146 on stroma cells conveys an engraftment-facilitating effect. Clonal MDS cells have been propagated for periods beyond 6 months and have been transplanted successfully into secondary recipients. Engraftment of human clonal MDS cells with stem cell characteristics in immunodeficient mice is greatly facilitated by coinjection of stroma/mesenchymal cells, particularly with IV administration. CD146 expression on stroma is an essential factor; however, no model develops the laboratory and clinical features of human MDS. Additional work is needed to determine cellular and noncellular factors required for the full evolution of MDS. The objective of is this article is to review murine xenotransplantation models for myelodysplastic syndromes (MDS). The difficulties in achieving sustained engraftment of MDS cells in immunodeficient mice may lie in innate characteristics of the MDS clones and microenvironmental factors. Engraftment of very low numbers of CD45+ clonal MDS cells has been achieved with intravenous injection; higher rates of engraftment are obtained via the intramedullary route. Coinjection of certain stroma components with hematopoietic cells overcomes limitations of intravenous (IV) administration, allowing for engraftment of high proportions of human CD45+ cells in mouse spleen and marrow. Expression of CD146 on stroma cells conveys an engraftment-facilitating effect. Clonal MDS cells have been propagated for periods beyond 6 months and have been transplanted successfully into secondary recipients. Engraftment of human clonal MDS cells with stem cell characteristics in immunodeficient mice is greatly facilitated by coinjection of stroma/mesenchymal cells, particularly with IV administration. CD146 expression on stroma is an essential factor; however, no model develops the laboratory and clinical features of human MDS. Additional work is needed to determine cellular and noncellular factors required for the full evolution of MDS. Myelodysplastic syndromes (MDS) are clonal diseases of hematopoietic stem/precursor cells. The incidence in the United States is estimated at 3.5–12.6 per 100,000 per year [1Rollison D.E. Howlader N. Smith M.T. et al.Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs.Blood. 2008; 112: 45-52Crossref PubMed Scopus (507) Google Scholar, 2Ma X. Does M. Raza A. Mayne S.T. Myelodysplastic syndromes: incidence and survival in the United States.Cancer. 2007; 109: 1538-1542Crossref Scopus (423) Google Scholar, 3Polednak A.P. Trend (1999-2009) in U.S. death rates from myelodysplastic syndromes: Utility of multiple causes of death in surveillance.Cancer Epidemiol. 2013; 37: 569-574Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar], but the incidence increases with age, reaching 30–50 per 100,000 per year in persons older than 70 years, a population in whom it may be the most frequent hematologic malignancy [2Ma X. Does M. Raza A. Mayne S.T. 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Edwin D. et al.Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice.Cancer Res. 2006; 66: 5029-5038Crossref PubMed Scopus (41) Google Scholar] to induce a murine disease that can mimic the human disorder or to use immunodeficient mice that accept the implantation or injection of human tissue or cells and allow for in vivo propagation (i.e., xenotransplantation) [17Kerbauy D.M.B. Lesnikov V. Torok-Storb B. Bryant E. Deeg H.J. Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-b2microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells (Letter to the Editor).Blood. 2004; 104: 2202-2203Crossref PubMed Scopus (48) Google Scholar, 18Nilsson L. Åstrand-Grundström I. Anderson K. et al.Involvement and intrinsic deficiencies of hematopoietic stem cells in MDS patients with trisomy 8.Blood. 2001; 98 (#1491): 354aGoogle Scholar, 19Li X. Marcondes A.M. Ragoczy T. 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Loken M.R. et al.NOD/SCID mice transplanted with marrow from patients with myelodysplastic syndrome (MDS) show long-term propagation of normal but not clonal human precursors.Leuk Res. 2003; 27: 425-436Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 23Nilsson L. Astrand-Grundstrom I. Arvidsson I. et al.Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level.Blood. 2000; 96: 2012-2021PubMed Google Scholar]. Consistent with those observations is the fact that few, if any, MDS-derived myeloid cell lines that do not require growth factor support have been established [24Thanopoulou E. Cashman J. Kakagianne T. Eaves A. Zoumbos N. Eaves C. Engraftment of NOD/SCID-b2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome.Blood. 2004; 103: 4285-4293Crossref PubMed Scopus (80) Google Scholar, 25Takagi S. 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In vivo models of human diseases offer many advantages over in vitro studies by allowing longitudinal observations and possible treatment interventions in an environment closer to the human in vivo situation than in vitro experiments. However, as indicated already, propagation of clonal CD34+ cells derived from the marrow of patients with MDS has been difficult [17Kerbauy D.M.B. Lesnikov V. Torok-Storb B. Bryant E. Deeg H.J. Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-b2microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells (Letter to the Editor).Blood. 2004; 104: 2202-2203Crossref PubMed Scopus (48) Google Scholar, 18Nilsson L. Åstrand-Grundström I. Anderson K. et al.Involvement and intrinsic deficiencies of hematopoietic stem cells in MDS patients with trisomy 8.Blood. 2001; 98 (#1491): 354aGoogle Scholar, 22Benito A.I. Bryant E. Loken M.R. et al.NOD/SCID mice transplanted with marrow from patients with myelodysplastic syndrome (MDS) show long-term propagation of normal but not clonal human precursors.Leuk Res. 2003; 27: 425-436Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 23Nilsson L. Astrand-Grundstrom I. Arvidsson I. et al.Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level.Blood. 2000; 96: 2012-2021PubMed Google Scholar]. Table 1 summarizes several published murine xenotransplantation models of MDS.Table 1Murine xenotransplantation models of MDSModelMouse strainTransplanted MDS cellsAdded stroma supportTBI dose (cGy)Clonal markerInjection routeProportion of mice with engraftmentReference1NOD/SCIDCD34+/CD38−None350–375del(5q)IV1/721Agliano A. Martin-Padura I. Mancuso P. et al.Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains.Int J Cancer. 2008; 123: 2222-2227Crossref PubMed Scopus (137) Google Scholar2NOD/SCIDβ2mnullCD34+/CD38−None350–375+8IV0/716Fenske T.S. McMahon C. Edwin D. et al.Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice.Cancer Res. 2006; 66: 5029-5038Crossref PubMed Scopus (41) Google Scholar3NOD/SCIDBMMCNone300, 350, 375Multiple clonesIV or IP34/4820Sanchez P.V. Perry R.L. Sarry J.E. et al.A robust xenotransplantation model for acute myeloid leukemia.Leukemia. 2009; 23: 2109-2117Crossref PubMed Scopus (94) Google Scholar4NOD/SCIDβ2mnullBMMCNone350del(5q); +8IV31/4322Benito A.I. Bryant E. Loken M.R. et al.NOD/SCID mice transplanted with marrow from patients with myelodysplastic syndrome (MDS) show long-term propagation of normal but not clonal human precursors.Leuk Res. 2003; 27: 425-436Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar5NOD/SCIDβ2mnullBMMCHS5+HS27a stroma cells325del(5q); del(7q); -YIM11/1515Funk R.K. Maxwell T.J. Izumi M. et al.Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG–PML/RARA transgenic mice.Blood. 2008; 112: 1434-1442Crossref PubMed Scopus (13) Google Scholar6NOD/SCID IL2Rγnull (NOD)∗Nomenclature as used by the authors.WBMCD34+/CD33+hCD45+Mesenchymal stem cells250Multiple clonesIM20/3143Mhyre A. Marcondes A.M. Spaulding E.Y. Deeg H.J. Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD.Blood. 2009; 113: 649-658Crossref PubMed Scopus (31) Google Scholar7Nod.cg-Prkdcscid IL2rgtm1wjll (NSG)∗Nomenclature as used by the authors.BMMCHS27a stroma cells275Multiple clonesIV44/4617Kerbauy D.M.B. Lesnikov V. Torok-Storb B. Bryant E. Deeg H.J. Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-b2microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells (Letter to the Editor).Blood. 2004; 104: 2202-2203Crossref PubMed Scopus (48) Google ScholarBMMC = bone marrow mononuclear cells; IM = intramedullary; IP = intraperitoneal; IV = intravenous; MDS = myelodysplastic syndrome; WBM = whole bone marrow cells.∗ Nomenclature as used by the authors. Open table in a new tab BMMC = bone marrow mononuclear cells; IM = intramedullary; IP = intraperitoneal; IV = intravenous; MDS = myelodysplastic syndrome; WBM = whole bone marrow cells. Nilsson et al. [23Nilsson L. Astrand-Grundstrom I. Arvidsson I. et al.Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level.Blood. 2000; 96: 2012-2021PubMed Google Scholar] reported on transplantation of human CD34+ cells from seven patients with MDS whose karyotypes all contained deletion of the long arm of chromosome 5 (5q-) into NOD/SCID mice irradiated with 350–375 cGy. Only mice receiving CD34+ cells (7 × 105 ) from one individual patient showed engraftment of intravenously (IV) injected cells, showing up to 12% CD45+ human cells in bone marrow [23Nilsson L. Astrand-Grundstrom I. Arvidsson I. et al.Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level.Blood. 2000; 96: 2012-2021PubMed Google Scholar]. The same investigators then reported transplantation of CD34+CD38− cells from patients with early-stage MDS, all with karyotypes containing trisomy 8 (+8), and none showed engraftment [18Nilsson L. Åstrand-Grundström I. Anderson K. et al.Involvement and intrinsic deficiencies of hematopoietic stem cells in MDS patients with trisomy 8.Blood. 2001; 98 (#1491): 354aGoogle Scholar]. Our own earlier studies showed that nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice irradiated with 350–375 cGy and transplanted with IV-injected MDS marrow allowed for long-term propagation of normal but not clonal MDS cells, suggesting that the NOD/SCID environment was not conducive to the expansion of clonal MDS precursors [22Benito A.I. Bryant E. Loken M.R. et al.NOD/SCID mice transplanted with marrow from patients with myelodysplastic syndrome (MDS) show long-term propagation of normal but not clonal human precursors.Leuk Res. 2003; 27: 425-436Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. Thanopoulou et al. [24Thanopoulou E. Cashman J. Kakagianne T. Eaves A. Zoumbos N. Eaves C. Engraftment of NOD/SCID-b2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome.Blood. 2004; 103: 4285-4293Crossref PubMed Scopus (80) Google Scholar] reported engraftment of neoplastic cells with multilineage potential from patients with MDS in NOD/SCID mice, which also had β2 microglobulin deleted (NOD/SCID-β2−/− mice), and in four cases the regenerating cells in recipient mice showed the same clonal markers as the original MDS samples [24Thanopoulou E. Cashman J. Kakagianne T. Eaves A. Zoumbos N. Eaves C. Engraftment of NOD/SCID-b2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome.Blood. 2004; 103: 4285-4293Crossref PubMed Scopus (80) Google Scholar]. Importantly, these immunodeficient mice were also transgenic for the human hematopoietic growth factors interleukin (IL) 3, granulocyte-macrophage colony-stimulating factor and steel factor, the relevance of which was stressed more recently in a report by Takagi et al. [25Takagi S. Saito Y. Hijikata A. et al.Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation.Blood. 2012; 119: 2768-2777Crossref PubMed Scopus (80) Google Scholar]. The authors suggested that the genetic alteration of MDS clonal cells could affect patterns of differentiation and responsiveness to hematopoietic growth factors, and that NOD/SCID-β2m−/− mice would be superior to NOD/SCID mice for xenotransplant experiments [24Thanopoulou E. Cashman J. Kakagianne T. Eaves A. Zoumbos N. Eaves C. Engraftment of NOD/SCID-b2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome.Blood. 2004; 103: 4285-4293Crossref PubMed Scopus (80) Google Scholar]. Hematopoietic stem cells are maintained by biochemical and physical contextual signals from the microenvironment consisting of osteoblasts, mesenchymal/stroma cells, endothelial cells, pericytes, and macrophages, in addition to matrix structures and soluble factors [29Raaijmakers M.H.G.P. Mukherjee S. Guo S. et al.Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia.Nature. 2012; 464: 852-857Crossref Scopus (797) Google Scholar, 30Raaijmakers M.H. Scadden D.T. Evolving concepts on the microenvironmental niche for hematopoietic stem cells (Review).Curr Opin Hematol. 2008; 15: 301-306Crossref PubMed Scopus (69) Google Scholar, 36Konopleva M. Konoplev S. Hu W. Zaritskey A.Y. Afanasiev B.V. Andreeff M. 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Ferraro F. et al.Mesenchymal and haematopoietic stem cells form a unique bone marrow niche.Nature. 2010; 466: 829-834Crossref PubMed Scopus (2342) Google Scholar]. Disruption of components of the niches will alter hematopoiesis. For example, Raaijmakers et al. [29Raaijmakers M.H.G.P. Mukherjee S. Guo S. et al.Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia.Nature. 2012; 464: 852-857Crossref Scopus (797) Google Scholar] showed that deletion of Dicer 1 in murine osteoblast progenitors resulted in the development of dysplastic murine hematopoiesis. Others showed that in the presence of clonal MDS cells marrow stroma can exhibit abnormal gene expression and function [39Ferrer R.A. Wobus M. List C. et al.Mesenchymal stromal cells from patients with myelodyplastic syndrome display distinct functional alterations that are modulated by lenalidomide.Haematologica. 2013; 98: 1677-1685Crossref PubMed Scopus (61) Google Scholar, 40Geyh S. Oz S. Cadeddu R.P. et al.Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells.Leukemia. 2013; 27: 1841-1851Crossref PubMed Scopus (152) Google Scholar]. Those data support the concept that the microenvironment is essential both in normal and in pathologic hematopoiesis and show that bidirectional signals between hematopoietic cells and the microenvironment affect hematopoiesis. Working with two established stroma cell lines, HS5 and HS27a, derived from a healthy marrow donor [41Roecklein B.A. Torok-Storb B. Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes.Blood. 1995; 85: 997-1005Crossref PubMed Google Scholar], we showed in an in vitro coculture system that apoptosis-resistant clonal MDS progenitors from patients with advanced MDS acquired sensitivity to apoptosis induced by TNF-α following stroma contact [42Bhagat T.D. Spaulding E. Sohal D. et al.MDS marrow stroma is characterized by epigenetic alterations.Blood. 2008; 112 (#3635): 1243Google Scholar, 43Mhyre A. Marcondes A.M. Spaulding E.Y. Deeg H.J. Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD.Blood. 2009; 113: 649-658Crossref PubMed Scopus (31) Google Scholar, 44Li X. Marcondes A.M. Gooley T.A. Deeg H.J. The helix-loop-helix transcription factor TWIST is dysregulated in myelodysplastic syndromes.Blood. 2010; 116: 2304-2314Crossref PubMed Scopus (37) Google Scholar]. However, hematopoietic precursors that remained adherent to stroma remained viable [43Mhyre A. Marcondes A.M. Spaulding E.Y. Deeg H.J. Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD.Blood. 2009; 113: 649-658Crossref PubMed Scopus (31) Google Scholar, 45Kerbauy D.M.B. Mhyre A. Bryant E. Deeg H.J. Do MDS-derived clonal hematopoietic precursors require human stroma support for survival.Curr Res Hematol. 2007; 1: 1-13Google Scholar]. Strikingly, normal hematopoietic precursors did not become sensitive to apoptosis upon stroma contact [43Mhyre A. Marcondes A.M. Spaulding E.Y. Deeg H.J. Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD.Blood. 2009; 113: 649-658Crossref PubMed Scopus (31) Google Scholar, 44Li X. Marcondes A.M. Gooley T.A. Deeg H.J. The helix-loop-helix transcription factor TWIST is dysregulated in myelodysplastic syndromes.Blood. 2010; 116: 2304-2314Crossref PubMed Scopus (37) Google Scholar]. Based in part on these in vitro observations, Kerbauy et al. [17Kerbauy D.M.B. Lesnikov V. Torok-Storb B. Bryant E. Deeg H.J. Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-b2microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells (Letter to the Editor).Blood. 2004; 104: 2202-2203Crossref PubMed Scopus (48) Google Scholar] used NOD/SCID-β2m−/− mice conditioned with total body irradiation of 325 cGy, and they showed engraftment of distinct clonal MDS-derived hematopoietic precursors when stroma cells (HS5 and HS27a cells combined) were coinjected via the intramedullary (IM) route; the proportion of human cells in peripheral blood, determined at 4 to 17 weeks, was 0.7–58.4% (median 8.9%) [17Kerbauy D.M.B. Lesnikov V. Torok-Storb B. Bryant E. Deeg H.J. Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-b2microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells (Letter to the Editor).Blood. 2004; 104: 2202-2203Crossref PubMed Scopus (48) Google Scholar]. More recently, Muguruma et al. [46Muguruma Y. Matsushita H. Yahata T. et al.Establishment of a xenograft model of human myelodysplastic syndromes.Haematologica. 2011; 96: 543-551Crossref PubMed Scopus (28) Google Scholar] injected bone marrow CD34+ cells from patients with MDS (or AML), together with or without human mesenchymal stem cells, into the medullary space of NOD/SCID mice with deletion of the T cell receptor λ chain (NOD/SCID/IL2Rγ−/− [NOG]) mice irradiated with 250 cGy [46Muguruma Y. Matsushita H. Yahata T. et al.Establishment of a xenograft model of human myelodysplastic syndromes.Haematologica. 2011; 96: 543-551Crossref PubMed Scopus (28) Google Scholar]. The CD34+ cells were obtained from six patients with MDS and eight patients with AML with various cytogenetic abnormalities, including −7, +8 and complex abnormalities [46Muguruma Y. Matsushita H. Yahata T. et al.Establishment of a xenograft model of human myelodysplastic syndromes.Haematologica. 2011; 96: 543-551Cross
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