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

Abstract

Myelodysplastic syndromes represent particularly challenging hematologic malignancies that arise from a large spectrum of genetic events resulting in a disease characterized by a range of different presentations and outcomes. Despite efforts to classify and identify the key genetic events, little improvement has been made in therapies that will increase patient survival. Animal models represent powerful tools to model and study human diseases and are useful pre-clinical platforms. In addition to enforced expression of candidate oncogenes, gene inactivation has allowed the consequences of the genetic effects of human myelodysplastic syndrome to be studied in mice. This review aims to examine the animal models expressing myelodysplastic syndrome-associated genes that are currently available and to highlight the most appropriate model to phenocopy myelodysplastic syndrome disease and its risk of transformation to acute myelogenous leukemia. ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.069385 ABSTRACTMouse models myelodysplastic syndrome human candidate genes haematologica | 2013; 98 (1) 11 Figure 1. Mouse models to study malignant hematologic disease. Several strategies can be employed to create mouse models of disease. Candidate genes can be introduced into the germline under the control of appropriate promoters to drive expression in certain cell compartments. Knock-out strategies create gene deficient mice, whilst knock-in strategies use the endogenous promoters; but again these tend to be conditional systems requiring specific promoters to determine in which cell the genes are introduced. Transduction of bone marrow and reinfusion is a powerful tool. Xenograft models are theoretically the best if the techniques involved can be improved.

Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis

“…Given this, it is likely that the haploinsufficiency for multiple interacting genes leads to altered hematopoietic differentiation and function in 5A3 +/del mice. Similar to the 5A3 +/del mice described here, other mutations found in MDS patients perturb hematopoiesis, but do not consistently induce hematologic disease in the absence of cooperating mutations ( Beurlet et al, 2013 ). This is not unexpected given the advanced age of most MDS patients and the presence of multiple genetic lesions in diseased BM.…”

Stem and progenitor cell alterations in myelodysplastic syndromes

“…30 The ongoing advances in xenografting of patient-derived MDS HSPCs and the generation of induced pluripotent HSCs from patients with MDSs will help advance our understanding of the disease in future studies. 31,32 New cell surface markers can potentially identify aberrant MDS stem cells Because histological examination cannot differentiate between preleukemic and healthy HSCs, recent studies have attempted to uncover specific markers of aberrant HSPCs in MDSs. Use of parallel transcriptional profiling using multiple populations of FACS-sorted HSCs and progenitors from a large number of AML and MDS samples and age-matched healthy controls led to the discovery of interleukin-1 (IL-1) receptor accessory protein (IL1RAP) as a cell surface antigen that was overexpressed on HSCs and GMPs that were part of the malignant clone, including preleukemic stem cells and progenitors.…”

Myelodysplastic syndrome patient-derived xenografts: from no options to many

“…MDS is a very heterogeneous group of blood disorders, associated with lesions in dozens of driver genes. 2,3 Genetically engineered mouse models harboring mutations in the most common MDS driver genes display several characteristics of MDS [11][12][13] but remain imperfect as an experimental tool since they generally only recapitulate a subset of the phenotypes associated with human MDS. During the past few decades, in particular during the past 5 years, we have seen several improvements in the toolbox available for the generation of MDS PDX.…”

“…These include strains harboring lesions in the most commonly mutated genes in MDS, such as SF3B1, 6 TET2, 7,8 ASXL1 9 and SRSF2. 10 The phenotypic properties of these models have been reviewed in detail previously [11][12][13] and although they all present with several phenotypic features of MDS, they clearly have some limitations with respect to their abilities to recapitulate human MDS biology. As an example, Sf3b1 K700E mutant mice develop anemia and display expansion of the long-term hematopoietic stem cell compartment, consistent with an MDS phenotype.…”