CHARACTERIZATION OF THERAPY-INSENSITIVE LSC SUBPOPULATIONS IN CHRONIC MYELOID LEUKEMIA

In chronic myeloid leukemia (CML), a rare subset of leukemic stem cells (LSC) persists in patients responding to conventional tyrosine kinase inhibitor (TKI) therapy. The failure to eradicate these LSCs results in indefinite therapy dependence and a risk of leukemic relapse. However, the conventional LSC compartment (Lin-CD34+CD38-) is highly heterogeneous where only a sub population is believed to be functional, TKI-insensitive LSCs. Previously, using single-cell gene expression analysis we characterized the heterogeneity within the LSC population (Lin-CD34+CD38-) in CML patients. Interestingly, by comparing LSC heterogeneity at diagnosis with the heterogeneity following 3 months of TKI therapy we uncovered a therapy-insensitive, quiescent LSC-subpopulation, which could be isolated at high-purity using a combination of the surface markers: Lin-CD34+CD38-CD45RA-cKIT-CD26+ (Warfvinge, Geironson, Sommarin et al., 2017). Here, we expand the single-cell analysis of CML LSC populations to include combined immunophenotype-/RNA sequencing analysis (CITE-seq). By comparing LSCs from patients with different therapeutic outcome we describe how LSC heterogeneity at diagnosis correlate with long-term therapy response. We furthermore evaluate the potential for humanized ossicle-niche xenotransplantation (Reinisch et al., 2016) as a model system for functional characterization of LSC subpopulations in vivo.