The blood system is a hierarchically organized tissue with hematopoietic stem cells (HSCs) at the apex. These stem cells replenish the immune system by generating as many as a trillion cells per day of the myeloid, lymphoid and erythrocyte/megakaryocyte lineages. We develop single-cell technologies to assess blood cell function in health and disease. The simultaneous acquisition of genetic, epigenetic and transcriptional features from single cells provides an opportunity to assess the molecular makeup of the blood at unprecedented resolution. In particular, we are applying these technologies to study age-related changes in the immune system, including genetic mutations that cause clonal hematopoiesis and altered inflammatory signaling. Understanding how these changes relate to disease can lead to the rational design of therapeutic interventions.
Image adapted from Guilliams et al., Immunity 2018.

The acquisition of genetic mutations that confer a competitive advantage to stem cells can cause a pre-malignant clonal expansion and, coupled with signaling and environmental changes, lead to the development of cancer. We aim to understand the evolution of leukemia cells, how they adapt to stress and how they subvert the anti-tumor immune response. Specifically, we are investigating how leukemia cells leverage stress signaling to survive FLT3 inhibitors that have been approved for the treatment of acute myeloid leukemia (AML). We also use blastic plasmacytoid dendritic cell neoplasms (BPDCN) as a model of tumor evolution and interactions between tumor cells and the immune system. We plan to leverage a molecular understanding of resistance and relapse mechanisms to design therapies that effectively eradicate tumor cells.