Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal

Area of Science:

• Molecular Biology
• Cancer Research
• Stem Cell Biology

Background:

• Alternative splicing networks in human embryonic stem cells are implicated in cell reprogramming.
• Muscleblind-like (MBNL) RNA binding proteins normally repress these embryonic splicing programs.

Purpose of the Study:

• To investigate the role of MBNL3 in the malignant reprogramming of progenitor cells into chronic myeloid leukemia stem cells (CML).
• To identify therapeutic targets for eliminating these reprogrammed malignant stem cells.

Main Methods:

• RNA sequencing
• Splice isoform-specific quantitative RT-PCR
• Lentiviral transduction
• In vivo humanized mouse models

Main Results:

• Reduced MBNL3 expression promoted malignant reprogramming of progenitors into self-renewing blast crisis CML stem cells (BC LSCs).
• MBNL3 knockdown led to overexpression of CD44 transcript variant 3 (CD44v3) and increased BC LSC proliferation.
• Combined inhibition of CD44 and BCR-ABL1 suppressed LSC maintenance in a niche-dependent manner.

Conclusions:

• MBNL3 down-regulation triggers an embryonic alternative splicing program, characterized by CD44v3 overexpression, driving malignant progenitor reprogramming.
• This mechanism offers a novel target for selective detection and elimination of BC LSCs in their microenvironment.