RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• Age-related hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing contribute to secondary acute myeloid leukemia (AML).
• While DNA mutations are linked to AML in older adults, the role of RNA processing in hematopoietic stem and progenitor aging and leukemia stem cell (LSC) generation is unclear.

Purpose of the Study:

• To investigate the contribution of RNA processing alterations to hematopoietic stem and progenitor aging and LSC generation.
• To identify RNA splice isoform patterns distinguishing normal and malignant hematopoietic progenitors.
• To evaluate the therapeutic potential of splicing modulation in AML.

Main Methods:

• Comprehensive RNA sequencing and splice-isoform-specific PCR were used to analyze RNA splice isoform expression patterns.
• Splicing reporter assays and pre-clinical patient-derived AML models were employed.
• Pharmacologic splicing modulator 17S-FD-895 was tested.

Main Results:

• Distinct RNA splice isoform expression patterns differentiated normal young/aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors.
• Treatment with 17S-FD-895 reversed pro-survival splice isoform switching in AML models.
• 17S-FD-895 significantly impaired LSC maintenance.

Conclusions:

• RNA processing alterations play a role in HSPC aging and LSC generation.
• Therapeutic splicing modulation, alongside monitoring splice isoform biomarkers, could prevent leukemia relapse.
• Splicing modulation represents a potential safe and effective strategy for preventing leukemia-related mortality.