Binder Lab

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and although treatment has improved over the last several decades, a substantial fraction of children still relapse, with poor outcomes. It is imperative that we develop better strategies to define high risk patients upfront and to identify novel therapies to prevent relapse. There is growing evidence that leukemic cells (LC) “reprogram” their surrounding niche cells to protect themselves from cytotoxic chemotherapy, but little is known about the molecular signaling pathways that are involved.

We hypothesize that LCs from early-relapse patients (ER-LCs) utilize the microenvironment more efficiently and via different molecular mechanisms when compared with LCs from patients who did not relapse (NR-LCs).

To study the complex microenvironment of leukemic cells, we use the zebrafish (Danio rerio) as a model organism. About 82% of disease associated genes have a counterpart in zebrafish and especially the hematopoietic system is highly conserved to humans. This makes the zebrafish an excellent model to study leukemia. In parallel to hematopoietic development in mammals, there are different hematopoietic niches throughout zebrafish development, that are highly conserved in their cellular composition. During the larval stage, the caudal hematopoietic tissue (CHT) serves as the site of hematopoiesis. This vessel bed is located in the caudal part of the fish and highly suitable for in vivo microscopy due to the transparency of zebrafish larvae.

We established xenografts of primary pediatric leukemia patient samples into zebrafish larvae. Fluorescently labeled cells are transplanted into different niche-transgenic reporter larvae and the leukemic niche is analyzed over time by multidimensional confocal microscopy. Thereby, we aim to develop a biological score representing differences in localization patterns, migration behavior and specific cell interactions, which we correlate to their underlying molecular pathways by applying next generation sequencing. With this approach, we directly translate biological observations into a microenvironmental gene signature. Ultimately the goal is to identify novel therapeutic targets in protective leukemia-niche interactions that may improve outcomes in these children.