Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in...

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Chemotherapy can induce remission in cancer but often leaves resistant cells, leading to relapse.
• While xenograft models suggest chemoresistance mechanisms in acute myeloid leukemia (AML), their prevalence in human patients is unclear.

Purpose of the Study:

• To investigate cellular and molecular features of chemoresistance in human acute myeloid leukemia (AML) patients post-chemotherapy.
• To identify potential biomarkers for chemoresistant leukemia stem cells.

Main Methods:

• Single-cell RNA sequencing of paired pre- and post-chemotherapy bone marrow samples from 13 pediatric AML patients.
• Transcriptomic profiling to distinguish AML cells from normal cells and identify specific cell populations.

Main Results:

• Leukemia stem cell (LSC) and oxidative phosphorylation (OXPHOS) signatures were found in approximately 50% of leukemic populations, correlating with therapy tolerance.
• The transmembrane receptor CD69 was highly expressed in chemoresistant hematopoietic stem cell (HSC)-like populations (CD69+ HSC-like subpopulation).
• CD69 overexpression suppressed mTOR signaling, promoting cell quiescence and adhesion; CD69+ HSC-like cells were linked to poor prognosis in AML patients.

Conclusions:

• Leukemia stem cell (LSC) properties and OXPHOS are significant chemoresistance factors in human AML.
• CD69 shows potential as a biomarker for identifying chemoresistant leukemia stem cells.
• These findings offer insights for developing strategies to target residual, chemo-surviving AML cells.