Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics.

Area of Science:

• Hematology
• Cancer Biology
• Stem Cell Research
• Genomics

Background:

• Cancer stem cells (CSCs) are crucial drivers of tumor progression and recurrence in various cancers.
• Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) are implicated in mortality but are challenging to isolate due to low numbers and similarity to healthy hematopoietic stem cells (HSCs).
• Effective eradication of cancer requires a deep understanding and characterization of CSCs.

Purpose of the Study:

• To develop a method for identifying and molecularly profiling LSCs, HSCs, and pre-leukemic stem cells in AML.
• To distinguish between healthy and cancerous stem cells and characterize stem and progenitor cell populations.
• To identify LSC-specific gene expression programs and understand differentiation blocks caused by leukemic mutations.

Main Methods:

• Integration of single-cell transcriptomics with lineage tracing techniques.
• Utilized both nuclear and mitochondrial somatic variants for lineage tracing.
• Combined mutational status analysis with gene expression profiling at the single-cell level.

Main Results:

• Successfully identified and molecularly profiled LSCs, HSCs, and pre-leukemic stem cells.
• Mutational status effectively discriminated between healthy and cancerous cells.
• Gene expression patterns distinguished between stem cell and progenitor cell populations, revealing LSC-specific programs and differentiation block mechanisms.

Conclusions:

• Single-cell multi-omic approaches, combining transcriptomics and lineage tracing, are powerful tools for characterizing cancer stem cells.
• This methodology enables the identification of LSC-specific molecular signatures and the mechanisms underlying AML pathogenesis.
• The findings pave the way for improved strategies targeting the root cause of AML.