Advances in the application of patient-derived xenograft models in acute leukemia resistance

Abstract

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are genetically heterogeneous malignancies of hematopoietic stem cells, characterized by complex mutations and a high risk of drug resistance and relapse. Patient-derived xenograft (PDX) models are dynamic entities transplanted with leukemia stem cells (LSCs), retaining patients' biological and genetic characteristics. By elucidating LSCs, clonal dynamics, and microenvironment interaction, PDXs facilitate the preclinical evaluation of therapy sensitivity, including immunotherapies, epigenetic therapies, and other agents targeting mutated proteins or apoptosis. The application of PDXs has provided translational evidence for various studies with reliable clinical relevance. Additionally, conventional PDXs remain a robust tool in identifying drug resistance compared with other models, and their potential is further unleashed when examined in large cohorts or combined with novel technologies, which not only enhances our understanding of acute leukemia biology but also enables the discovery and identification of novel biomarkers. In this review, we present the application of PDX models for acute leukemia resistance, including mechanism investigation, therapy evaluation, and associated challenges.

Keywords: Patient-derived xenografts; acute leukemia; leukemia stem cells.

Figure 1

The establishment and application of acute leukemia PDXs. The general process of constructing the acute leukemia PDX model involves sample collection (according to immunophenotypes or mononuclear cell population), pretreatment (if necessary), injection into immunodeficient mice, and subsequent engraftment monitoring. The well-accomplished engraftment enables further studies on acute leukemia, including LSCs, clonal dynamics, heterogeneity, and microenvironment interaction involving MSCs, OBs, ADs, and relative cytokines. In preclinical experiments, PDXs are invaluable tools for identifying therapy sensitivity in translational research. The PDX model has been proven to be a significant platform for evaluating various acute leukemia therapies, including targeted agents, immunotherapies, and other novel therapies. Adapted from Smart Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0; annotations and color modifications were added by the authors using Adobe Illustrator 2024. PDXs: Patient-derived xenografts; LSCs: leukemia stem cells; MSCs: mesenchymal stem cells; OBs: osteoblasts; ADs: adipocytes.