Page 22 - Haematologica April 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):864-869
Myelodysplastic syndrome patient-derived xenografts: from no options to many
Christophe Côme,1,2,3 Alexander Balhuizen,1,2,3 Dominique Bonnet4 and Bo T. Porse1,2,3
1The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Denmark; 2Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark; 3Danish Stem Cell Center (DanStem), Faculty of Health Sciences, University of Copenhagen, Denmark and 4Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK
Introduction
According to the recently updated tumor classification by the World Health Organization, myelodysplastic syndrome (MDS) constitutes a heterogeneous group of blood disorders characterized by cytopenia and dysplasia in at least one of the myeloid lineages.1 MDS is most common in the elderly and is caused by inefficient hematopoiesis and increased apoptosis within the bone marrow (BM). It is a genet- ically heterogeneous disorder and individual cases generally harbor two to three mutations in one of approximately 30 driver genes which are recurrently mutated in MDS.2,3 Of importance, many of these genes have also been found to be mutated in acute myeloid leukemia (AML), with frequencies of mutations differing between the two diseases.2,4 The spectrum of survival of patients with MDS is broad and high-risk MDS is associated with an increased propensity to progression to AML.5
There has been considerable emphasis on the development of genetically engi- neered mouse models in attempts to study MDS. These include strains harboring lesions in the most commonly mutated genes in MDS, such as SF3B1,6 TET2,7,8 ASXL19 and SRSF2.10 The phenotypic properties of these models have been reviewed in detail previously11-13 and although they all present with several pheno- typic features of MDS, they clearly have some limitations with respect to their abil- ities to recapitulate human MDS biology. As an example, Sf3b1K700E mutant mice develop anemia and display expansion of the long-term hematopoietic stem cell compartment, consistent with an MDS phenotype. However, the Sf3b1K700E mutant line fails to present with ring sideroblasts which are normally found in patients with SF3B1 mutations.14 Another likely contributor to the inability of current genetically engineered mouse model lines to fully recapitulate the phenotypic spectrum of MDS is the fact that most models typically harbor one genetic lesion and, therefore, not the full mutational complement observed in MDS patients. Thus, there is a clear need for better models of MDS biology, including patient-derived xenografts (PDX), in order to recapitulate the disease’s biology and complexity better.
The history of myelodysplastic syndrome patient-derived xenografts
The first PDX models of AML were established more than 40 years ago by sub- cutaneously engrafting patient material into immune-deprived mice.15 More physi- ologically relevant models were developed over the next decade via the use of tail vein injection and improved immune-deficient strains.16,17 In contrast, it was not until the beginning of this millennium that cells from MDS patients were demon- strated to engraft functionally in immune-compromised mice.18-20 However, only cells from a limited number of patients could be engrafted and a study with a large number of patients demonstrated that engraftment was sustained by residual nor- mal cells and not by the MDS clone(s).21 During the last decade, several laboratories have published a number of complementary approaches for the generation of MDS PDX.22-34 Importantly, these combined efforts have demonstrated the engraftment capacity of most MDS subtypes,23-28,34 that the expanded cells retain the genetic and phenotypic features of the primary tumor,24-27,29,30,32,34 that these PDX models also sus- tain engraftment in secondary recipients24,27,29,34 and that they allow evaluation of new therapies.32,33 Nevertheless, as summarized in Table 1 and Figure 1, these mod- els are quite heterogeneous. Specifically, several immune-compromised murine strains have been used (NOG, NSG, NSG-S or MISTRG) and injected at different ages (from newborn pups to adult animals). Moreover, a number of different cell
Correspondence:
BO T. PORSE
bo.porse@finsenlab.dk
Received: October 9, 2019. Accepted: November 27, 2019. Pre-published: March 19, 2020.
doi:10.3324/haematol.2019.233320
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