Contribution of Inflammation to the Pathogenesis of RUNX1-FPDMM

PROJECT SUMMARY: Overall
The long-term goal of this Program is to define mechanisms of acquired drug resistance in acute myeloid
leukemia (AML) so that novel drug combinations can be deployed to prevent disease relapse and improve patient
outcomes. The overall five-year survival rate for AML remains 20%, an outcome that has not changed for several
decades. Although seven new regimens have been approved for AML in recent years, the improved initial
remission rates with these therapies do not lead to durable outcomes. Disease relapse is fueled by a complex
cross-talk of tumor cells adapting with support from the bone marrow microenvironment. The investigators of this
proposed ARTNet Center have collaborated for 15+ years, including as a Center in the DRSN consortium – the
predecessor to ARTNet. Our prior work has involved development of the largest-to-date functional genomic
dataset on AML patient samples, genome-wide CRISPR screens, broad studies of AML interactions with stromal
and immune cells, and testing of diverse drug combinations. These studies have led to >150 collaborative
publications, continuous collaborative funding for 15+ years, creation of numerous large datasets deposited into
public repositories, and translation of findings into numerous clinical trials. Our overarching hypothesis is that
the architecture of acquired drug resistance is governed by temporal extrinsic and intrinsic factors and
elucidating this trajectory will allow for the identification of properly timed therapeutic strategies to stave
off acquired resistance and stay ahead of tumor evolution and adaptation. This hypothesis will be tested
through three well integrated Projects addressing the following questions: 1) How does AML tumor cell intrinsic
biology adapt to evade therapeutic pressure? We will use genome-wide CRISPR platforms as well as long-term
progenitor expansion of primary AML patient samples to understand feedback pathways and shifting epigenetic
and cell state landscapes that can drive acquired drug resistance. 2) How does the stromal and immune
microenvironment govern drug resistance? We will use co-culture and advanced bone marrow models to perform
genome-wide screens and test the impact of single-agents on AML-microenvironment cross-talk. Through
computational modeling, we will nominate targeting strategies to mitigate tumor extrinsic resistance signals and
boost immune anti-tumor responses. 3) How can resistance signatures and drug combinations be effectively
clinically translated? We will use high-throughput and advanced, engineered models of human bone marrow to
test and prioritize drug combinations from targets in Projects 1 and 2. We will also study longitudinal specimens
from patients enrolled on ongoing clinical trials. All of these data will inform and refine the work of Projects 1 and
2. Our Center will be supported by an Administrative Core and a Functional Phenotyping Core. Collectively, we
will develop a comprehensive understanding of acquired drug resistance in AML and identify new regimens to
treat patients at the earliest possible stage, prevent relapse, and achieve durable remissions.

Grant Number: 3U54CA224019-08S1
NIH Institute/Center: NIH
Principal Investigator: Anupriya Agarwal