Leukemic cells reside in the bone marrow microenvironment (BMM). This complex entity consists of various cell types, the extracellular matrix, cytokines, and chemical factors, all of which can contribute to AML maintenance and therapy resistance. Bone marrow adipocytes (BMAds) constitute the largest cell population in the BMM by volume, and their number expands during aging. Our objective is to understand the role of host autophagy pathways in the establishment and maintenance of the AML microenvironment, with a focus on autophagy in bone marrow adipocytes as the dominant population of BMM cells. We utilize in vitro and in vivo models of BMAd-AML interaction, as well as specialized assays to profile selective autophagy receptor candidates and autophagosome cargoes.

Chemotherapy failure due to primary therapy resistance represents a significant clinical challenge in the treatment of patients with AML. Some patterns of primary treatment resistance show AML cell persistence despite on-target therapy and are not well-explained by acquired genetic mutations, or by the failure to eradicate leukemic stem cells. Instead, data from our lab and others point towards rapid acquisition of temporary, reversible drug tolerance due to nongenetic cellular adaptation. We are interested in further understanding this process and are applying a toolbox of molecular and cellular technologies to obtain a comprehensive overview of the pathways and mechanisms involved.

Precision oncology aims to match specific mutations identified by NGS to treatments targeting aberrant pathways. However, a major impediment to its successful implementation in molecular tumor boards is the paucity of available functional information for many identified somatic mutations. Our aim is to integrate available genomic information with global phosphoproteomics to measure pathway activation, annotate variants of unknown significance, and identify predictive biomarkers for drug response.