Engraftment of NOD/SCID-β2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome

Abstract

The development of immunodeficient mouse xenograft models has greatly facilitated the investigation of some human hematopoietic malignancies, but application of this approach to the myelodysplastic syndromes (MDSs) has proven difficult. We now show that cells from most MDS patients (including all subtypes) repopulate nonobese diabetic-severe combined immunodeficient (scid)/scid-␤2 microglobulin null (NOD/SCID-␤2m ؊/؊ ) mice at least transiently and produce abnormal differentiation patterns in this model. Normal marrow transplants initially produce predominantly erythroid cells and later predominantly B-lymphoid cells in these mice, whereas most MDS samples produced predominantly granulopoietic cells. In 4 of 4 MDS cases, the regenerated cells showed the same clonal markers (trisomy 8, n ‫؍‬ 3; and 5q؊, n ‫؍‬ 1) as the original sample and, in one instance, regenerated trisomy 8 ؉ B-lymphoid as well as myeloid cells were identified. Interestingly, the enhanced growth of normal marrow obtained in NOD/SCID-␤2m ؊/؊ mice engineered to produce human interleukin-3, granulocyte-macrophage colony-stimulating factor, and Steel factor was seen only with 1 of 7 MDS samples. These findings support the concept that human MDS originates in a transplantable multilineage hematopoietic stem cell whose genetic alteration may affect patterns of differentiation and responsiveness to hematopoietic growth factors.

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

“…82 In another study, the results of MDS sample engraftment suggested the presence of a relatively late type of 'multilineage but myeloid-restricted' neoplastic 'stem' cell with repopulating activity, limited self-renewal ability, and skewed differentiation potential. 83 These findings also show that the repopulating cells present in MDS patients include residual normal or pre-neoplastic repopulating cells with normal features that outcompete the neoplastic clone if adequately stimulated. Recently, a transgenic approach has provided evidence that disturbance of the endosteal niche can result in MDS.…”

Transplantation of a myelodysplastic syndrome by a long-term repopulating hematopoietic cell

“…In a modified study, modest engraftment (Ͻ5%) of cells with clonal markers characteristic of the MDS clone was detected 13-17 weeks after intramedullary transplant of cells into NOD/SCID/␤2 microglobulin (NOD/SCID-␤2m null ) mice (15). Investigators using NOD/SCID-␤2m null mice that were engineered to express human IL3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and Steel Factor (SF) demonstrated that BM cells from 9 of 11 MDS patients generated detectable levels of human hematopoietic cells (14). However, engraftment was transient in some cases, clonal markers indicated that 15-99% of the cells were derived from normal hematopoietic cells, and there was no evidence that the mice developed peripheral blood cytopenias or other evidence of clinical MDS.…”

“…Although MDS has been recognized as a disease entity for 50 years (13) and is considered to be a clonal stem cell disorder, efforts to verify this hypothesis using xenograft mouse transplantation models have failed, because the MDS cells either engraft poorly or not at all (14)(15)(16), and the mice do not develop clinical evidence of MDS. These results stand in contrast to those obtained with AML, in which the disease can be readily transplanted into immunodeficient mice (17); these xenotransplant assays have been crucial for the identification of a subset of cells that can transfer leukemia to immunodeficient recipients; referred to as leukemia-initiating cells (L-ICs) (17,18).…”

Development of Cytogenetic Abnormalities in Myelodysplastic Syndromes

“…Involvement of non-myeloid lineages is controversial as some research report MDS associated chromosome abnormalities in T-cell, B-cell, or natural killer-cell populations while some other reports claim for the absence of such chromosome aberrations in lymphoid lineages [40,41]. While MDS has very rare chance of evolving into lymphoid acute leukemia, it is noteworthy to indicate that as most of the research have proven; the dysplasia and aberrations are more prominent in cells committed to myeloid lineages [42]. However, some reports argue that only del 5q could be seen at more primitive HSCs and other aberrations like trisomy 8 might occur at later stages in the hematopoietic hierarchy [40,43].…”

“…The common recurring cytogenetic abnormalities in MDS include del(5q), -7/del(7q), -8,-18/del (18q), del (20q),-5,-Y,-17/del (17p) including isochromosome (17q), -21, inv/t(3q), -13/del (13q), -1/del (1q), -21, -11, del (12p), t(5q), del (11q), and t(7q) [1,2,[35][36][37][38][39][40][41][42][43]. The initiator hematopoietic cell with cytogenetic abnormalities in the hierarchy of hematopoiesis is yet to be identified.…”