Scholarlink

<p>Tumor growth and relapse are often driven by cancer stem cells, but self-renewal mechanisms and genetic mutations that elevate their number are not fully understood. Here, we show that recurrent L122R mutation (Leucine to Argine change at amino acid 122) in the DNA-binding site of the Myogenic Differentiation 1 (MYOD1) transcription factor increases cancer stem cell frequency in aggressive Spindle cell/sclerosing rhabdomyosarcoma. MYOD1<sup>L122R</sup> also makes tumors resistant to chemotherapy and radiation. Epigenetic analysis reveals that MYOD1<sup>L122R</sup> binds MYC-like DNA recognition motifs to activate stem cell programs, while retaining some wild-type function to regulate muscle pathways that drive transformation. Mechanistically, MYOD1<sup>L122R</sup> transcriptionally activates <i>Receptor tyrosine kinase-like Orphan Receptor 2 (ROR2)</i> to turn on the non-canonical Wingless/Integrated (WNT) planar cell polarity pathway to increase both cancer stemness and therapy resistance. Targeting ROR2 with antibody-drug conjugates kills MYOD1<sup>L122R</sup>-mutated tumor cells, offering therapeutic opportunities. These findings provide insights into how MYOD1<sup>L122R</sup> rewires rhabdomyosarcoma to a stem-like state and defines a unique class of oncogenic transcription factors found in aggressive cancers.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

MYOD1 mutation drives cancer stem cell pathways and therapy-resistance in spindle cell/sclerosing rhabdomyosarcoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月3日

查看全文
  • Yun Wei,
  • Luis Antonio Corchete Sánchez,
  • Sabateeshan Mathavarajah,
  • Diego Antelo,
  • Shuze Wang,
  • Jihee Lee,
  • Alexander Daiki Weissman,
  • Devika D. Kannambadi,
  • Qian Qin,
  • Sara G. Danielli,
  • Elisa J. Quantin,
  • Tiffany C. Eng,
  • Alexandra Veloso,
  • Yueyang Wang,
  • Gunnlaugur P. Neilsen,
  • Chuan Yan,
  • Valerie Shiwen Yang,
  • Anand G. Patel,
  • Selene C. Koo,
  • Patience Odeniyide,
  • Christine A. Pratilas,
  • Miguel N. Rivera,
  • Esther Rheinbay,
  • David M. Langenau

摘要

Tumor growth and relapse are often driven by cancer stem cells, but self-renewal mechanisms and genetic mutations that elevate their number are not fully understood. Here, we show that recurrent L122R mutation (Leucine to Argine change at amino acid 122) in the DNA-binding site of the Myogenic Differentiation 1 (MYOD1) transcription factor increases cancer stem cell frequency in aggressive Spindle cell/sclerosing rhabdomyosarcoma. MYOD1L122R also makes tumors resistant to chemotherapy and radiation. Epigenetic analysis reveals that MYOD1L122R binds MYC-like DNA recognition motifs to activate stem cell programs, while retaining some wild-type function to regulate muscle pathways that drive transformation. Mechanistically, MYOD1L122R transcriptionally activates Receptor tyrosine kinase-like Orphan Receptor 2 (ROR2) to turn on the non-canonical Wingless/Integrated (WNT) planar cell polarity pathway to increase both cancer stemness and therapy resistance. Targeting ROR2 with antibody-drug conjugates kills MYOD1L122R-mutated tumor cells, offering therapeutic opportunities. These findings provide insights into how MYOD1L122R rewires rhabdomyosarcoma to a stem-like state and defines a unique class of oncogenic transcription factors found in aggressive cancers.