High-risk blood malignancies such as acute myeloid leukemia or advanced chronic lymphocytic leukemia remain difficult-to-treat clinical challenges. Immunotherapies including allogeneic stem cell transplantation or targeted immunomodulation using immune checkpoint blockade can provide long-term disease control, but their success rate is still not satisfactory. Single cell genomics is an approach that can effectively monitor immune and leukemia cell dynamics by providing detailed insight into changes in cellular compositions, cell states and interactions. This work provides examples how integrated immune and leukemia monitoring at single cell resolution reveals the determinants of response or non- response to immunotherapy and tracks the clonal evolution of malignant cell populations as therapeutic resistance develops. It also furthers the toolkits available to us by extending standard single cell RNA sequencing with targeted genotyping and explores the ability to utilize mitochondrial DNA mutations as an alternative natural barcoding system for the study of leukemic subclones. Together, this sets the stage for more stream-lined single cell studies that foreshadow the adoption of these technologies into clinical hematologic practice.
