There is high heterogeneity among therapy-persistent leukemic stem cells (LSCs) with differences in response to tyrosine kinase inhibitor (TKI) therapy among patients with newly diagnosed chronic myeloid leukemia (CML), according to a study published in Blood.1

A proportion of leukemic stem cells remain insensitive to TKI therapy, resulting in relapse after treatment completion. This study used high-throughput immunophenotypic screens and single-cell gene expression analysis to characterize LSCs and to evaluate the effect of TKI therapy on LSC subpopulations.

The study included 22 patients with chronic phase CML and 5 age-matched healthy volunteers.

LSCs from patients with CML demonstrated a high number of differentially expressed markers by flow cytometry compared with LSCs from healthy patients.

Gene expression analysis of 2151 single LSCs identified 7 subpopulations of LSCs among CML samples. The subpopulations were identified based on their expression of genes related to myeloid commitment, myeloid program, the cell cycle, lymphoid-related genes, megakaryocytic/erythroid program, and lineage molecules.

The seventh subpopulation, which expressed a primitive, quiescent molecular program, demonstrated the lowest response to TKI treatment.

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TKI therapy resulted in more LSCs of specific subpopulations: those that expressed the primitive molecular program, early myeloid commitment, or a megakaryocytic/erythroid program. TKI insensitivity was also associated with the phenotype LinCD34+CD38-/lowCD45RA-cKIT-CD26+.

The authors wrote that the identification of LinCD34+CD38-/lowCD45RA-cKIT-CD26+ cells offers “possibilities for characterization of therapy-insensitivity in CML” and may be a “potential therapeutic target for improved therapy response.”

Reference

  1. Warfvinge R, Ulfsson LG, Sommarin MNE, et al. Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML. Blood. 2017 Jan 25. [Epub ahead of print]