# Identification of therapeutic targets for leukemia stem cells in AML-iPSC models

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $652,184

## Abstract

PROJECT SUMMARY/ABSTRACT
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.
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## Key facts

- **NIH application ID:** 10348154
- **Project number:** 5R01CA225231-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Michael Kharas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $652,184
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348154

## Citation

> US National Institutes of Health, RePORTER application 10348154, Identification of therapeutic targets for leukemia stem cells in AML-iPSC models (5R01CA225231-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348154. Licensed CC0.

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