Developing Acute Myeloid Leukemia Models with Diverse Ancestral Origins

Project Summary Acute myeloid leukemia (AML) is an aggressive cancer of the bone marrow. There is a well-documented survival disparity with non-Hispanic white (NHW) patients having a better outcome compared to non-Hispanic black (NHB) patients. To date, clinical trials with minimal NHB patient participation are the basis for all approved treatments and risk stratification systems. How ancestral racial backgrounds are reflected in AML that arises in NHB patients is largely unknown. This may have led to treatment practices that are not optimal for NHB patients. Indeed, in contrast to NHWs who have a good prognosis, NHB patients with NPM1 mutations have an adverse prognosis when treated with standard therapies. The lack of preclinical models of NHB origins further exacerbate this lack of knowledge. As a result, there is little to no preclinical or clinical evidence to what extent the current approved therapies in AML are efficacious in NHB patients. This is clearly unacceptable. This proposal seeks to leverage novel approaches to generate preclinical AML models of NHB origins and to compare therapy responses and basic biochemical properties to models generated from NHW patients. This will be accomplished in the 3 aims of this proposal. They are 1) Utilize the Sleeping Beauty (SB) transposon system to generate AML models from CD34+ cells derived from healthy donors of NHB and NHW origins; 2) Characterize racial differences in therapy sensitivity and DNA damage response in AML models; 3) Develop patient derived organoid models from NHW and NHB AML patients; The results from this study will greatly inform the influence of racial ancestry on AML arising from NHB patients. This information will guide new strategies geared specifically towards AML in NHB patients and will inform drug development efforts to ensure future therapies are efficacious for AML patients of all racial backgrounds.