Single-Cell Analysis: Understanding Myeloid Malignancies and Disease Risk

Sandra S. Zinkel, MD, PhD
Associate Professor of Medicine and Cell & Developmental Biology, Vanderbilt University

Over the past several years, there have been major advances in the use of single cell analysis in understanding hematopoietic development and hematologic diseases. In a joint session of the Scientific Committees on Myeloid Biology and Myeloid Neoplasia, experts will explore the role of this technology in understanding myeloid lineage commitment, the bone marrow niche, subclonal complexity in myeloid malignancies, as well as how it can be applied in measuring disease burden and residual disease. Here, session co-chair Sandra S. Zinkel, MD, PhD, from Vanderbilt University, previews the session highlights, including future goals of the research.

Why is single-cell analysis being featured in this session?

We are interested in presenting the cutting-edge technology that is allowing transformative insights into the basic biology of hematopoiesis, risk of hematopoietic disease, and risk of disease recurrence. Vijay G. Sankaran, MD, PhD, from Boston Children’s Hospital, will start the session by presenting his work using large-scale, population-based studies, such as genome-wide association studies, to identify how genetic variation can affect the risk of developing blood disorders. Timm Schroeder, PhD, from ETH Zurich, will discuss using state-of-the-art imaging analysis to understand how the bone marrow microenvironment and architecture influences hematopoietic stem and progenitor cell function. Margaret Goodell, PhD, from Baylor College of Medicine, will review how specific mutations in a key driver gene in clonal hematopoiesis and myelodysplastic syndromes (MDS) affect disease risk and disease evolution. Finally, Konstanze Döhner, MD, from University Hospital of Ulm, will discuss how single-cell analysis can be applied to determine disease burden, and the implications for management of hematopoietic disease.

How is this technology being used today to grow our understanding of hematopoiesis?

Single-cell technology has provided numerous insights into the mechanisms underlying cell fate decisions. Hematopoietic differentiation is now understood to occur in a continuum of states, rather than in discrete steps. Advances in imaging analysis have helped us understand how the location of stem and progenitor cells directs differentiation and maintains stem cell function. Genomic technologies have revealed regulatory networks and epigenomic changes important for normal hematopoiesis, which change during aging or disease.

We also have made great progress in identifying which genes are mutated in hematopoietic diseases such as MDS and acute myeloid leukemia (AML). The identification of these genes led to the appreciation that normal individuals develop clonal hematopoiesis, or expansion of clones containing these disease-associated mutations, and the presence of clonal hematopoiesis confers increased disease risk. Population-based studies are beginning to provide insight into the influence of genetic variation on hematopoiesis and risk of disease.
Finally, the field is now learning how to use these new technologies to identify residual disease and help inform therapy in hematopoietic malignancies.

Where is this technology headed in the future?

With respect to hematopoiesis, the technology is headed toward providing a comprehensive understanding of how hematopoiesis is regulated. We are also learning how this regulation is perturbed in aging and in disease by looking at the impact of genetic variation at a population level, spatial organization within the bone marrow, and mutational alterations of key driver genes. Ultimately, the goal is to leverage this knowledge to inform therapeutic decisions and to identify individuals at risk for development of hematopoietic disease.

Single Cell Analysis of Hematopoietic Development and Clonal Complexity of Malignant Hematopoiesis 

Live Q&A: Saturday, December 5, 2020
9:30 a.m. – 10:15 a.m., Pacific time