Acute Myeloid Leukemia (AML) is a highly aggressive blood cancer with median overall survival of ~1 year. Although most patients respond to treatment with chemotherapy initially, many subsequently relapse. The malignant cells in AML display a hierarchical organization with leukemia stem cells (LSCs) residing in the apex. LSCs are believed to be a prominent source of chemotherapy resistance and AML relapse, because they have distinct biological properties than the bulk AML population and are therefore presumably resistant to most conventional therapies. Thus therapies specifically targeting LSCs could theoretically give more lasting responses or even cures. Although there is substantial evidence for the existence of both murine and human LSCs, significant challenges to their study exist. LSCs are currently defined by their functional properties in mouse or xenotransplantation models. Their similarities to normal hematopoietic stem cells (HSCs), their rarity and the unavailability of specific immunophenotypic markers that distinguish LSCs from the rest of AML cells makes their prospective isolation, study and use in drug discovery challenging. We (Papapetrou laboratory) have pioneered the modeling of myeloid malignancies with induced pluripotent stem cells (iPSCs). We recently derived the first iPSC models of AML (AML-iPSCs). In close collaboration with the Kharas laboratory, we found that the hematopoietic stem/progenitor cells (HSPCs) derived from AML- iPSCs recapitulate salient features of LSCs, such as high proliferation potential, multipotentiality, serial engraftment of a lethal leukemia in immunodeficient mice and hierarchical organization giving rise to phenotypic and functional heterogeneity. Thus AML-iPSC models enable for the first time genome-wide integrative molecular analyses, large-scale screening and in vitro and in vivo validation in relevant LSC-like human cells. In this application we will use these very novel AML-iPSC models to identify key molecular mechanisms sustaining LSC properties that may constitute promising therapeutic targets. The proposed studies leverage the unique expertise of the Papapetrou lab in iPSC modeling, combined with the expertise of the Kharas lab in studying molecular mechanisms of myeloid malignancy and can generate new insights into LSC biology and identify new therapeutic targets for future drug development. !
Leukemia stem cells (LSCs) are believed to be a major source of chemotherapy resistance and disease relapse in acute myeloid leukemia (AML) and their therapeutic targeting could result in sustained responses or even cures, however their prospective isolation for use in drug discovery is challenging. Our groups (Papapetrou/Kharas) recently developed induced pluripotent stem cells (iPSCs) from AML patients, which recapitulate cardinal features of LSCs. In the proposed studies we will combine forces to generate new insights into LSC biology and identify new therapeutic targets.
| Papapetrou, Eirini P (2018) Modeling myeloid malignancies with patient-derived iPSCs. Exp Hematol : |
