Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• Inflammation-associated base deaminases contribute to therapeutic resistance in cancers.
• The specific role of these enzymes in the evolution of pre-leukemia stem cells (pre-LSCs) to acute myeloid leukemia stem cells (LSCs) remains unclear.

Purpose of the Study:

• To investigate the role of APOBEC3C and ADAR1 in the progression of pre-LSCs to LSCs.
• To identify the molecular mechanisms driving this evolution in myeloproliferative neoplasms (MPNs).

Main Methods:

• Comparative whole-genome and whole-transcriptome sequencing of FACS-purified pre-LSCs from MPN patients.
• Lentiviral overexpression of APOBEC3C and knockdown of ADAR1.
• JAK2/STAT3 inhibition using ruxolitinib or fedratinib.

Main Results:

• APOBEC3C upregulation, increased C-to-T mutations, and HSPC proliferation were observed during pre-LSC to LSC progression.
• Inflammatory splice isoform overexpression and ADAR1p150-induced RNA editing correlate with APOBEC3C upregulation.
• STAT3 editing, STAT3β isoform switching, and elevated phospho-STAT3 characterize LSC evolution, preventable by JAK2/STAT3 inhibition or ADAR1 knockdown.

Conclusions:

• Primate-specific APOBEC3C drives pre-LSC proliferation and contributes to LSC evolution.
• ADAR1-mediated splicing deregulation is a critical factor in pre-LSC to LSC transformation.
• Targeting APOBEC3C and ADAR1 pathways may offer therapeutic strategies for MPNs and AML.