PROJECT SUMMARY:
The objective of this multi-principal investigator application is to leverage the complimentary expertise of the
investigators to develop and credential multiple new mouse models of high-risk, pediatric acute myeloid leukemia
(AML). These will include both human and mouse AML with genotypes and cells of origin that are informed by
real-world patient data and represent understudied high-risk molecular subtypes of the disease. This proposal
will address a pressing clinical and scientific need. Children with AML continue to have an overall poor survival
relative to other pediatric cancer patients. Advances in targeted therapies have been slow to develop, and up-
front treatment protocols have remained remarkably stagnant for the past 4 decades. Efforts to derive new
therapies have lagged, in part due to the marked genetic heterogeneity of pediatric AML. Indeed, we have
established that there are over 20 unique molecular subtypes of pediatric AML that reflect unique driver mutations
and expression signatures. Pediatric AML also harbor secondary mutations that further exacerbate genetic
heterogeneity. Thus, therapies that might benefit patients with one genetic subtype of pediatric AML could have
limited value in a different patient population. Unfortunately, current models of pediatric AML do not reflect the
marked genomic diversity observed in patients. Current approaches commonly focus on a limited subset of
molecular subtypes, typically avoiding rare high-risk subtypes, and they either do not co-model secondary
mutations or they implement mutational combinations that are not reflected in patients. Thus, there remains a
clear unmet need to advance pediatric AML modeling as a means to expand genetically informed therapeutic
options. We will address this need through the completion of three Aims that exploit the unique skills of each
investigator’s independent research programs and the exceptional institutional infrastructures at both St. Jude
Children’s Research Hospital and Washington University School of Medicine. Aim 1: Develop novel syngeneic
mouse models of high-risk pediatric AML; Aim 2: Develop human models of rare pediatric AMLs with patient-
informed cooperating mutations; Aim 3. Credential established and newly developed AML models against one
another and primary human specimens. To create AML models, we will deploy several innovative genetic
strategies, including a novel approach to generate genetically complex murine AML from induced pluripotent
stem cells and direct editing of human cord blood progenitors. Credentialing will involve a direct comparison of
primary patient material with genetically matched murine and human models based on transcriptomic,
epigenomic and proteomic strategies. The high-risk pediatric AML models developed through this
comprehensive, cross-species proposal will provide the scientific community with an unparalleled collection of
extensively characterized specimens for future investigations into disease mechanisms and therapeutic
vulnerabilities.