Fine-Tuning Patient-Derived Xenograft Models for Precision Medicine Approaches in Leukemia

Abstract

Many leukemias are characterized by well-known mutations that drive oncogenesis. Mice engineered with these mutations provide a foundation for understanding leukemogenesis and identifying therapies. However, data from whole genome studies provide evidence that malignancies are characterized by multiple genetic alterations that vary between patients, as well as inherited genetic variation that can also contribute to oncogenesis. Improved outcomes will require precision medicine approaches–targeted therapies tailored to malignancies in each patient. Preclinical models that reflect the range of mutations and the genetic background present in patient populations are required to develop and test the combinations of therapies that will be used to provide precision medicine therapeutic strategies. Patient-derived xenografts (PDX) produced by transplanting leukemia cells from patients into immune deficient mice provide preclinical models where disease mechanisms and therapeutic efficacy can be studied in vivo in context of the genetic variability present in patient tumors. PDX models are possible because many elements in the bone marrow microenvironment show cross-species activity between mice and humans. However, several cytokines likely to impact leukemia cells are species-specific with limited activity on transplanted human leukemia cells. In this review we discuss the importance of PDX models for developing precision medicine approaches to leukemia treatment. We illustrate how PDX models can be optimized to overcome a lack of cross-species cytokine activity by reviewing a recent strategy developed for use with a high-risk form of B-cell acute lymphoblastic leukemia (B-ALL) that is characterized by overexpression of CRLF2, a receptor component for the cytokine, TSLP.

PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia

“…In conclusion, pediatric T‐ALL cells largely maintain their DNA methylation pattern, their chromatin architecture, and most of their genomic characteristics when xenotransplanted into primary NSG mice. However, it must be noted that the absence of a normal immune system and the reduced ability of murine cytokines and chemokines to replace their human counterparts (Francis et al , ) result in an understimulation of immune pathways. The data presented in this report indicate these effects to reduce the chromatin accessibility in a small fraction of gene loci, as reflected by ~3.7% of the analyzed ATAC peaks, and to induce methylation in the small fraction of the gene promoters (0.17%).…”

The Generation and Application of Patient-Derived Xenograft Model for Cancer Research

“…In ovarian cancer, anti-cancer drugs were tested for precision medicine approach, using PDX model [ 56 ]. Also, fine-tuning PDX model for precision medicine was tried in consideration of cross-species cytokine in leukemia [ 57 ]. Collectively, the efforts to implement personalized medicine using PDX model (summarized in Fig.…”

Modeling the human bone marrow niche in mice: From host bone marrow engraftment to bioengineering approaches

“…Once the osteogenic ability of implanted cells was defined, the aim of these studies shifted to understanding the multipotency of hMSCs and their effect on the niche. The resulting human MSC carrier implants yielded human–mouse chimeric tissues colonized by mouse hematopoietic cells, suggesting this approach generates “humanized” microenvironments with niche properties, useful for hematopoietic studies and metastatic processes of various cancers ( Moreau et al, 2007 ; Lee et al, 2012 ; Bersani et al, 2014 ; Holzapfel et al, 2014 ; Čulen et al, 2015 ; Francis et al, 2016 ; Nelson and Roy, 2016 ; Theocharides et al, 2016 ; Aguado et al, 2017 ; Martine et al, 2017 ).…”