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Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma

Erin Butler1, Lin Xu2, Dinesh Rakheja2

  • 1University of Texas Southwestern Medical Center; erin.butler@utsouthwestern.edu.

Cold Spring Harbor Molecular Case Studies
|August 6, 2022
PubMed

Insights

Researchers found new alternative splicing in MYOD1 and MYF5 genes in rhabdomyosarcoma (RMS), a childhood cancer. This altered splicing disrupts muscle cell differentiation, potentially contributing to RMS development.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Developmental Biology

Background:

  • Rhabdomyosarcoma (RMS) is a pediatric cancer characterized by immature muscle cells, indicating a failure in skeletal muscle differentiation.
  • Transcription factors are crucial for skeletal muscle lineage commitment and differentiation.

Purpose of the Study:

  • To investigate potential defects in the differentiation program of RMS by searching for mRNA splicing variants in key muscle development transcription factors.
  • To identify alternative splicing events in MYOD1 and MYF5 genes in RMS tumors.

Main Methods:

  • Analysis of mRNA splicing variants in RMS tumor samples and cell lines using RNA-sequencing.
  • Complementary molecular analysis of MYOD1 mRNA.
  • Functional studies of the resulting MYOD1 variant protein (MYODΔEx2).

Main Results:

  • Identified exon 2 skipping in MYOD1 and MYF5 genes in RMS, but not in MYF6 or MYOG.
  • Confirmed exon skipping in MYOD1 in additional RMS cases.
  • Demonstrated that the MYODΔEx2 protein is less effective at inducing muscle-specific genes and confers a growth advantage in non-muscle cells and RMS xenografts.

Conclusions:

  • Alternative splicing, specifically exon skipping in MYOD1 and MYF5, is a previously unrecognized mechanism contributing to altered transcription factor function in RMS.
  • These splicing alterations may play a role in the pathogenesis of rhabdomyosarcoma by impairing terminal muscle differentiation.
Keywords:
Alveolar rhabdomyosarcomaEmbryonal rhabdomyosarcoma

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