# Impact of mutational order on molecular mechanisms of oncogenesis

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $665,262

## Abstract

PROJECT SUMMARY/ABSTRACT
Human cancers develop through the successive acquisition of somatic mutations which give rise to clonal cell
populations that outgrow normal cells through a reiterative process of clonal selection and evolution. While the
multi-step nature of oncogenesis has been long recognized, the fundamental principles that underlie this
process and determine its outcomes remain incompletely understood. It is now clear from large-scale
sequencing of cancer genomes that mutational co-occurrence and the relative timing of mutational acquisition
follow non-random patterns, but limited studies have addressed the impact of mutational order and cooperation
in biological or clinical outcomes.
Leukemogenesis offers an attractive case to model and study overarching principles of the clonal evolution.
Leukemias have very simple genomes, carrying very low numbers of driver genetic lesions compared to solid
tumors. More specifically, acute myeloid leukemia (AML) genomes can harbor as few as 2-3 driver genetic
lesions. My lab recently developed a model of clonal evolution of AML using sequential CRISPR-mediated
gene editing of human iPSCs. We found that by introducing 3 driver mutations into normal iPSCs (ASXL1 C-
terminus truncation, SRSF2P95L and NRASG12D SAR) we can create a “de novo” engraftable AML. Furthermore, our
preliminary data suggest that cooperation between specific mutations and/or the order of their acquisition
impose constraints on leukemogenesis.
The overarching goal of this proposal is to investigate the role of the order of mutational acquisition in the
clonal evolution of AML. In Aim 1, we will test the hypothesis that the initiating mutation establishes an
epigenetic landscape upon which the later mutation(s) need to act to establish a leukemic state in our iPSC
model and in primary human hematopoietic stem and progenitor cells (HSPCs). Aim 2 will define the minimum
number of mutations required for leukemogenesis. In Aim 3 we will explore the mechanistic constraints
underlying “obligatory late” signaling activating mutations by varying the order of acquisition of ASXL1, SRSF2
and NRAS mutations in our de novo oncogenesis model.
This work harnesses a unique myeloid leukemogenesis model developed in my laboratory to address
fundamental questions on the effects of mutational order on leukemogenesis and oncogenesis in general.

## Key facts

- **NIH application ID:** 10375146
- **Project number:** 1R01CA260711-01A1
- **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:** $665,262
- **Award type:** 1
- **Project period:** 2022-05-10 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375146

## Citation

> US National Institutes of Health, RePORTER application 10375146, Impact of mutational order on molecular mechanisms of oncogenesis (1R01CA260711-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375146. Licensed CC0.

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