Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies.

Ishnoor Sidhu,Anilkumar Gopalakrishnapillai,Sonali P Barwe,Raju K Pillai

doi:10.3390/cells10102698

Abstract

In vitro modeling of hematological malignancies not only provides insights into the influence of genetic aberrations on cellular and molecular mechanisms involved in disease progression but also aids development and evaluation of therapeutic agents. Owing to their self-renewal and differentiation capacity, induced pluripotent stem cells (iPSCs) have emerged as a potential source of short in supply disease-specific human cells of the hematopoietic lineage. Patient-derived iPSCs can recapitulate the disease severity and spectrum of prognosis dictated by the genetic variation among patients and can be used for drug screening and studying clonal evolution. However, this approach lacks the ability to model the early phases of the disease leading to cancer. The advent of genetic editing technology has promoted the generation of precise isogenic iPSC disease models to address questions regarding the underlying genetic mechanism of disease initiation and progression. In this review, we discuss the use of iPSC disease modeling in hematological diseases, where there is lack of patient sample availability and/or difficulty of engraftment to generate animal models. Furthermore, we describe the power of combining iPSC and precise gene editing to elucidate the underlying mechanism of initiation and progression of various hematological malignancies. Finally, we discuss the power of iPSC disease modeling in developing and testing novel therapies in a high throughput setting.

Highlights

Disease models provide a useful tool to deconstruct the alterations in the biological processes that lead to various kinds of hematological malignancies such as leukemia, lymphoma and multiple myeloma
The current review focuses on the development of induced pluripotent stem cells (iPSCs) models for understanding initiation and progression of hematological malignancies with a primary focus on using genetically engineered iPSCs as an alternative to patient-derived iPSCs
The understanding of human genetic disorders has been revolutionized with the development of patient-derived iPSCs especially for hematological diseases and cancer

Summary

Introduction

Disease models provide a useful tool to deconstruct the alterations in the biological processes that lead to various kinds of hematological malignancies such as leukemia, lymphoma and multiple myeloma. The use of reprogrammed induced pluripotent stem cells (iPSCs) has shown promise for the generation of custom-tailored cells for modeling hematological malignancies and drug screening [50] Their self-renewable property and the potential for differentiation into hematopoietic stem and progenitor cells (HSPCs) make iPSCs a cost-effective and scalable approach for disease modeling. The current review focuses on the development of iPSC models for understanding initiation and progression of hematological malignancies with a primary focus on using genetically engineered iPSCs as an alternative to patient-derived iPSCs. While the importance of hematopoietic differentiation of iPSC in disease modeling has been reviewed elsewhere [53,54], the present review highlights the development of 3-dimensional culture protocols for in vitro differentiation of iPSCs towards hematopoietic lineage

Disease Modeling Using Patient-Derived iPSCs

Disease Modeling Using Genetically Modified iPSCs

Clonal Evolution of AML

Down Syndrome-Myeloid Leukemia

Perspectives and Future Directions