# Mechanisms and therapeutic implications of human clonal hematopoiesis (CH) mutations

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $689,125

## Abstract

PROJECT SUMMARY/ABSTRACT
 In recent years, large-scale sequencing revealed that the presence of clonally expanded hematopoietic
stem/progenitor cells in the bone marrow and blood of healthy individuals is a widespread phenomenon in
humans, generally referred to as clonal hematopoiesis (CH). Clonally expanded hematopoietic cells in many
instances harbor mutations associated with myeloid malignancies and, importantly, their presence is
associated with increased risk of developing myeloid malignancies (myelodysplastic syndrome, MDS and
acute myeloid leukemia, AML). Leukemic progression is invariably associated with acquisition of additional
mutations by the CH clone and further clonal expansions. CH is thus a premalignant condition that often
constitutes the initiating event of leukemogenesis and thus offers a glimpse into the early events of malignant
transformation. However, there is a relative scarcity of models to study early events of leukemogenesis, as
mice do not develop CH and most human cancer models (immortalized cell lines, patient-derived xenografts)
capture advanced cancers. My lab has pioneered the modeling of myeloid malignancies with human induced
pluripotent stem cells (iPSCs). We recently developed a model of successive clonal evolution of AML.
 The overarching goal of this proposal is to investigate the molecular mechanisms underlying the
oncogenic effects of CH mutations. In the first Aim we will characterize cell-intrinsic (transcriptome, chromatin
accessibility, DNA methylation) and cell-extrinsic (cytokine secretion, differentiation propensity) effects of the 3
most common CH mutations – DNMT3A, TET2 and ASXL1 – using CRISPR-edited isogenic human iPSCs. In
the second Aim we will explore the role of cell competition in the clonal advantage of cells harboring CH
mutations before and after acquisition of additional mutations. In the third Aim, we will address the question of
whether fully transformed AML cells maintain or lose dependency upon the initial CH mutation using
engineered mutant alleles reversible via Cre-loxP recombination and testing the effects of correction of the CH
mutation on the initiation and maintenance of AML in vitro and in vivo in xenografts.
.

## Key facts

- **NIH application ID:** 10450238
- **Project number:** 1R01CA271331-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Eirini Papapetrou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $689,125
- **Award type:** 1
- **Project period:** 2022-06-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450238

## Citation

> US National Institutes of Health, RePORTER application 10450238, Mechanisms and therapeutic implications of human clonal hematopoiesis (CH) mutations (1R01CA271331-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10450238. Licensed CC0.

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