Scholarlink

<p>Juvenile myelomonocytic leukemia (JMML) is caused by constitutively activated RAS signaling and characterized by increased proliferation and predominant myelomonocytic differentiation of hematopoietic cells. Using <i>MxCre;Ptpn11</i><sup><i>D61Y</i>/+</sup> mice, which model human JMML, we show that RAS pathway activation affects apoptosis signaling through cell type-dependent regulation of BCL-2 family members. Apoptosis resistance observed in monocytes and granulocytes was mediated by overexpression of the anti-apoptotic and down-regulation of the pro-apoptotic members of the BCL-2 family. Two anti-apoptotic proteins, BCL-X<sub>L</sub> and MCL-1, were directly regulated by the oncogenic RAS signaling but, in addition, were influenced by microenvironmental signals. While BCL-X<sub>L</sub> and BCL-2 were required for the survival of monocytes, MCL-1 was essential for neutrophils. Interestingly, stem and progenitor cells expressing the oncogenic PTPN11 mutant showed no increased apoptosis resistance. BCL-X<sub>L</sub> inhibition was the most effective in killing myeloid cells in vitro but was insufficient to completely resolve myeloproliferation in vivo.</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

Oncogenic and microenvironmental signals drive cell type specific apoptosis resistance in juvenile myelomonocytic leukemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月8日

查看全文
  • Naile Koleci,
  • Ying Wu,
  • Niels Anton Wehner,
  • Jovana Rajak,
  • Venugopal Rao Mittapalli,
  • Julia Mergner,
  • Hui Xiao,
  • Jun Wang,
  • Madeleine Wahl,
  • Sheila Bohler,
  • Konrad Aumann,
  • Georg Häcker,
  • Senthilkumar Ramamoorthy,
  • Melanie Boerries,
  • Susanne Kirschnek,
  • Miriam Erlacher

摘要

Juvenile myelomonocytic leukemia (JMML) is caused by constitutively activated RAS signaling and characterized by increased proliferation and predominant myelomonocytic differentiation of hematopoietic cells. Using MxCre;Ptpn11D61Y/+ mice, which model human JMML, we show that RAS pathway activation affects apoptosis signaling through cell type-dependent regulation of BCL-2 family members. Apoptosis resistance observed in monocytes and granulocytes was mediated by overexpression of the anti-apoptotic and down-regulation of the pro-apoptotic members of the BCL-2 family. Two anti-apoptotic proteins, BCL-XL and MCL-1, were directly regulated by the oncogenic RAS signaling but, in addition, were influenced by microenvironmental signals. While BCL-XL and BCL-2 were required for the survival of monocytes, MCL-1 was essential for neutrophils. Interestingly, stem and progenitor cells expressing the oncogenic PTPN11 mutant showed no increased apoptosis resistance. BCL-XL inhibition was the most effective in killing myeloid cells in vitro but was insufficient to completely resolve myeloproliferation in vivo.