NEW YORK – Ohio State University and New York University have received grants amounting to just over $6 million from the US National Cancer Institute to study the genetic landscape and role of inflammation in acute myeloid leukemia.
Professors Ann-Kathrin Eisfeld and Elaine Mardis, both at Ohio State, received $3.43 million to build precision oncology approaches for the treatment of AML by identifying genetic variants and other genomic factors contributing to clinical risk stratification, which could also potentially be druggable and disease-modifying therapeutic targets.
The project will analyze frequently mutated genes in AML, especially focusing on how ancestry impacts gene variants' prognostic significance and how clinical risk classifications can then be adjusted to account for ancestry. The project also aims to determine whether previously unrecognized molecular features of these variants drive AML occurrence or therapy resistance.
The group undertaking this project hopes to build greater statistical confidence supporting frequently mutated AML genes and to develop more inclusive molecularly adjusted risk and treatment stratification tools for AML patients.
As part of the overall project, team members will analyze mutant variants of NPM1c, which are correlated with favorable outcomes in AML patients of Central European ancestry but with poor outcomes in people of other ancestries.
Eisfeld and Mardis' team will interrogate this genotype with single-cell multiomic assays to better differentiate bystander mutations from potential driver mutations, then test those mutant variants' roles in clonality or leukemia-stem-cell frequency and treatment response.
Eisfeld is also principal investigator on a $2.85 million grant awarded in July to Iannis Aifantis, chair of pathology at New York University Grossman School of Medicine. This grant will fund a project to identify molecular factors contributing to aberrant inflammation in AML, which may serve as targets for more precisely controlling disease progression and therapeutic response.
High inflammation within the bone marrow is associated with greater treatment resistance and poor survival in AML, but scientists have yet to discover how exactly such inflammation is triggered.
Aifantis and his colleagues have previously published studies showing that inflammation-related treatment resistance and mortality in AML appear to occur independently of other genetic factors, leading them to believe that targeting inflammation itself can improve treatment response and slow disease progression.
Collaborators on this project will use multiomic approaches to study patients with the highest and lowest degrees of inflammation from a well-characterized cohort of 1,600 AML patients with defined inflammatory states and compare their cell states, cell fates, and immune responses at the single-cell level.
They will also track how inflammatory, immune-regulatory, and associated clonal responses change in response to various treatments in longitudinally collected patient samples of select genotypes and in xenografts derived from those same patients. Xenografts will be serially profiled to enable direct comparison with the patient samples.
Finally, project members will test how well a class of anti-inflammatory agents called IL-1 inhibitors prevent inflammation-associated bone marrow remodeling and poor treatment response.
"Inflammation and the role of the immune system is an emerging topic in all cancer types, including AML," Eisfeld said in a statement. "This study will help us understand how inflammation shapes the clinical and molecular phenotypes of patients, including first insights into how we might be able to best target inflammation and overcome its adverse effects."