Deriving induced pluripotent stem cells from acute myeloid leukemia patients towards applications of autologous therapies and disease modeling

Abstract

Acute myeloid leukemia (AML) is a highly heterogeneous cancer with a poor prognosis. Clinical presentation is characterized by the abundant non-functional immature hematopoietic cells (blasts) in the bone marrow (BM) and peripheral blood (PB) of patients. Untreated, the rapid proliferation of these blasts contributes to hematopoietic system failure within months, leading to death. Although the standard chemotherapy regimen has remained relatively unchanged for decades and has proven to be effective at achieving initial remission induction, most patients succumb to relapse forming the basis of poor long-term survival. Incomplete mechanistic understandings of disease initiation, progression and maintenance of AML have impeded advances in therapy required for the improvement of long-term patient survival rates. This suggests that innovative and new model systems are required to understand the earliest initiation processes of AML disease towards more effective targeted therapy development. The ability to generate induced pluripotent stem cells (iPSCs) from human somatic cells provided a breakthrough in biomedicine to ‘capture’ diseased cells and their genome in a self-renewing state. Patient-derived human induced pluripotent stem cells (hiPSCs) have the theoretical ability to develop patient-specific (autologous) cell-based therapies and/or produce an endless number of specialized disease-associated cells, allowing replication of pathological characteristics of human disease in vitro. Despite the technical challenge of reprogramming human cancer cells due to the high inefficiency of the process compared to healthy samples, whereby iPSCs are often skewed in favor of residual normal cells over cells of the premalignant or malignant clone, I propose to develop a library of AML patient-derived iPSCs. Moreover, I hypothesize that pluripotent reprogramming can provide a unique alternative approach to dissect heterogeneity and molecular basis of AML that cannot be captured and studied in existing in vitro or in vivo patient-derived xenograft models. Additionally, I seek to investigate the ability of human iPSCs in the derivation of HSCs as a proof of concept for autologous cell-based therapies.