Explore niche-leukemic stem cell interactions and evaluate niche-directed leukemia treatments

About This Grant

Project Summary Title: Explore niche-leukemic stem cell interactions and evaluate niche-directed leukemia treatments. Retention of minimal residual leukemic stem cells (LSCs) within the bone marrow (BM) microenvironment, known as the niche, plays a pivotal role in therapeutic resistance and leukemia relapse. Our long-term goal is to unravel the intricacies of the niche and regulatory mechanisms governing human LSCs, identifying potential therapeutic targets within the tumor microenvironment to enhance leukemia treatment efficacy. We observed that dipeptidyl peptidase 4 (DPP4) deletion significantly alters LSC distribution in the AML BM and identified N-cadherin-expressing BM mesenchymal stem cells (N-cad+ MSCs) as critical in shaping LSC localization, essential for AML cell migration, stemness, and survival. We also discovered significant interactions between DPP4 on AML cells and glypican-3 (GPC3) on N-cad+ MSCs, regulating Cxcl12 activity and gradient. We hypothesize that molecular interactions between N-cad+ MSCs and LSCs are crucial for orchestrating LSC properties and are essential for effective human AML treatment. The objectives of this proposal are to elucidate the intricate crosstalk between N-cad+ MSCs and LSCs and evaluate niche-directed treatment strategies in both human and mouse AML models. Aim 1: Elucidate the molecular interactions between LSCs and niche cells. We will use inducible Gpc3 knockout in N-cad+ MSC mouse models to determine GPC3's role in AML development and LSC properties and study its impact on the crosstalk between N-cad+ MSCs and LSCs. Histological imaging and functional assays using AML patient BM biopsies will explore GPC3's role in the human LSC niche. Aim 2: Investigate the impact of N-cad+ MSC-derived Cxcl12 signaling on human LSC activity. We will perform scRNA-seq and histological imaging analysis of patient BM biopsies to identify whether N-cad+ MSCs are major CXCL12 sources in the BM niche for human LSCs. We will use AMD3100 treatment to block CXCL12 signaling in human LSCs, enabling us to evaluate the distinct properties of DPP4high and DPP4low LSCs in response to CXCL12. Aim 3: Evaluate niche-directed treatment strategies. We will compare chemotherapy efficacy between N-cad+ Cxcl12−/− and control AML mice and evaluate the stemness, survival, and localization of residual LSCs post- chemotherapy. Preclinical trials will assess the effects of niche-directed therapies on LSC activity, disease progression, and overall survival in AML patient-derived xenograft models using chemotherapy- resistant/relapsed AML cells.