Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research

Abstract

Key Points• With a few exceptions, the histologic and cytologic characteristics of myelodysplasia are similar in humans and mice.• As in humans, MDS and MDS/MPN are distinct diseases in mice; mouse models of these diseases can serve as useful research tools.Much-needed attention has been given of late to diseases specifically associated with an expanding elderly population. Myelodysplastic syndrome (MDS), a hematopoietic stem cell-based blood disease, is one of these. The lack of clear understanding of the molecular mechanisms underlying the pathogenesis of this disease has hampered the development of efficacious therapies, especially in the presence of comorbidities. Mouse models could potentially provide new insights into this disease, although primary human MDS cells grow poorly in xenografted mice. This makes genetically engineered murine models a more attractive proposition, although this approach is not without complications. In particular, it is unclear if or how myelodysplasia (abnormal blood cell morphology), a key MDS feature in humans, presents in murine cells. Here, we evaluate the histopathologic features of wild-type mice and 23 mouse models with verified myelodysplasia. We find that certain features indicative of myelodysplasia in humans, such as Howell-Jolly bodies and low neutrophilic granularity, are commonplace in healthy mice, whereas other features are similarly abnormal in humans and mice. Quantitative hematopoietic parameters, such as blood cell counts, are required to distinguish between MDS and related diseases. We provide data that mouse models of MDS can be genetically engineered and faithfully recapitulate human disease. (Blood. 2015;126(9):1057-1068

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

“…Primary human MDS cells grow poorly in most mouse models and highly specific and genetically engineered mouse models are required to study human MDS in the xenograft setting (Zhou et al , 2015). Consequently, to functionally assess the self‐renewal potential of both the CLEC12A positive CD34 + CD38 − cells and the CD34 + CD38 − cells lacking CLEC12A expression, four MDS patients with known clonal cytogenetic abnormalities were selected for studies in the LTC‐IC assay.…”

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

“…The effects of MDS mutations on HSCs are apparent in some mouse models 179 . For example, mutations in or loss of Dnmt3a or Tet2 expand the mutant HSC clone and increase HSC function at the expense of normal polyclonal hematopoiesis 75,77,180 .…”

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

“…Genetic mouse models recapitulate hallmark features of human MDS—including multi-lineage peripheral blood cytopenias, dysmyelopoiesis, and variable propensities for transformation to acute leukemia [84]—and therefore represent useful in vivo models to investigate the reciprocal interactions between MDS cells and their BMME. Moreover, recent studies of the hematopoietic niche in mice have identified specific populations of mesenchymal stromal cells, osteoblastic lineage cells, and endothelial cells that are critical for HSPC support [9–16].…”

“…NHD13 mice exhibit pathologic features of human MDS evidenced by multi-lineage blood cytopenias, dyspoiesis of erythroid, megakaryocytic and granulocytic cells and progression to acute leukemia [84, 88]. In studies of the NHD13 model, MSCs and OBCs were increased in the BMME of 18–23 week old NHD13 mice [89].…”