Comparison of chronic myeloid leukemia stem cells and hematopoietic stem cells by global proteomic analysis.

Tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the standard first-line therapy for patients with chronic-phase CML. However, TKIs cannot eliminate quiescent leukemia stem cells (LSCs) which persist in all patients on long-term therapy and provides a reservoir for disease progression and recurrence. Many researches have confirmed that TKI-resistant LSCs compartment can be captured within CD26  fraction. In order to analyze distinctive biological characteristics of TKI-resistant LSCs, we isolated the CD34  CD38CD26, CD34  CD38CD26and CD34  CD38  cells from 8 CML patients utilizing magnetic and flow sorting, and analyzed the global proteomic expression through high-resolution LC-MS/MS analysis. In the work, we discovered that a list of dysregulated proteins involved in energy metabolism and carcinogenesis, including PPARD, IL1-RAP, HNF, S15A2, PCLO, VA0D1, CKLF5, were extremely upregulated in the CD26  LSCs while some majoring in DNA mismatch repair or related to cell senescence, such as MLH3, NOLC1, were downregulated. Additionally, we verified the upregulation of PPARD in both CML patients-derived CD26  LSCs and donor-derived BCR-ABL1 overexpressed HSCs. These results open in turn new therapeutic avenues for targeting TKI-insensitive LSCs.