Elucidating the Spatial and Temporal Dynamics of Acute Myeloid Leukemia Progression Using Functional Omics and High-Throughput In Vivo Screening

Introduction

Advances in sequencing-based phylogenetic studies applied to cancer evolution have led to the observation that the linear accumulation of oncogenic alterations over individuals’ lifespan does not match the late life pattern of cancer incidence. It has thus become clear that beyond the sequential accumulation of oncogenic driver mutations, additional factors also support cancer outgrowth.

Key Factors in Cancer Evolution

The temporal and spatial dynamics of tumor evolution represent two of the most critical mutation-independent variables to consider. Hence, we hypothesized that the dual features of aging and spatial dissemination promote critical fitness gains that are at least as significant as driver mutations in cancer.

Project Goals

The goal of this proposal is to investigate the spatial and temporal determinants of tumor progression and to dissect the contributions of these processes to cancer pathogenicity.

Disease Model

Due to its quite unique occurrence pattern and propagation characteristics, Acute Myeloid Leukemia (AML) is the prototypical disease model that we have elected to template such spatiotemporal-dependent features of disease development.

Methodology

To study these features, we engineered two mouse models of leukemia dissemination and aging using serially-transplantable MLL-AF9-driven leukemic blasts. Using these two models, we propose to:

1. Combine metabolomic- and epigenomic-based profiling to portray the spatiotemporal dynamics of leukemia growth.
2. Deploy single-cell transcriptomics coupled with lineage tracing experiments to reveal the pre-deterministic attributes of such dynamics.
3. Leverage innovative multimodal in vivo shRNA and CRISPRa screening approaches to pinpoint and functionally characterize the critical age- and dissemination-related effector genes involved in leukemic progression.

Potential Impact

The comprehensive analysis of their unknown function will potentially define new therapeutic routes in AML, and, given the holistic nature of the spatiotemporal characteristics studied, in other cancers as well.