Studying the biology and therapeutic vulnerabilities of leukemia stem cells using AML-iPSCs

Eirini Papapetrou

PhD, MD

Icahn School of Medicine at Mount Sinai

Project Term: July 1, 2018 - June 30, 2023

Project Summary

Acute Myeloid Leukemia (AML) is a highly aggressive blood cancer with dismal overall survival rates. Although most patients initially respond to treatment with chemotherapy, many subsequently relapse. A prominent reason for relapse is the existence of leukemia stem cells (LSCs). While chemotherapy kills the bulk of the leukemia cells, LSCs are resistant and thus persist and re-grow the leukemia in due time. Thus, effective therapies leading to cures should target the LSCs. However, LSCs are rare and difficult to separate from the rest of the leukemia cells; therefore, their prospective isolation for use in mechanistic studies and drug discovery is challenging. My laboratory has pioneered a novel approach for the study of blood cancers that takes advantage of induced pluripotent stem cells (iPSCs). iPSCs are stem cells that we derive directly from AML patient cells through a recent breakthrough technology that reprograms the cells to replicate the features of the LSCs from those patients. They enable us to develop models of human diseases that offer many opportunities for laboratory studies that were not possible with prior disease models. iPSC models enable us to obtain human cells that capture disease features in unlimited numbers and perform experiments in large scale. My laboratory recently developed the first iPSC models of AML (AML-iPSCs) from patient cells. Interestingly, we found that we can easily isolate from them large numbers of cells with the cardinal features of LSCs, including the ability to transplant leukemia in mouse models. We are now poised to use these AML-iPSC models and the unique capabilities that they offer us for the first time to perform detailed and multifaceted analyses of the molecular circuitry that is critical for sustaining LSCs. We will generate AML-iPSCs from a number of different AML patients that have a variety of different molecular abnormalities, thus allowing us to study the diverse and heterogeneous AML subtypes found in patients. Our studies will utilize cutting-edge techniques to molecularly characterize these cells to better understand how they function. We will also use genetic screens to identify genes that may be targetable by drugs for potential therapy. Finally, we will use large collections of drug-like compounds to screen for chemicals that selectively kill AML-iPSCs while leaving healthy cells unscathed. We expect that these studies will identify key molecular mechanisms sustaining AML LSCs that we can exploit for their therapeutic targeting.