R01CA260711

Impact of Mutational Order on Molecular Mechanisms of Oncogenesis - 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 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 induced pluripotent stem cells (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.

Icahn School Of Medicine At Mount Sinai

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 100296504 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 383% from $665,262 to $3,211,950.