Scholarlink

<p>To address the cellular origin of ecotropic virus integration site 1 (EVI1)-expressing aggressive KMT2A-rearranged acute myeloid leukaemia (AML) we integrate an Evi1-GFP reporter allele in the inducible iKMT2A-MLLT3 mouse model. We observe that a single injection of thrombopoietin (TPO) selectively increases the number of cycling Evi1<sup>+</sup> haematopoietic stem cells (HSC) and accelerates AML initiation. Comparison of mouse Evi1<sup>+</sup> KMT2-MLLT3<sup>+</sup> AML originating from TPO-stimulated HSC with human EVI1<sup>+</sup>AML reveals higher expression of HSC genes including IL12Rβ2 and INPP4B linked to poor disease outcome of patients of four large AML cohorts. Knockdown experiments show exclusive MECOM-dependency of human EVI1<sup>high</sup> KMT2A-rearranged OCI-AML4 cells while reduction of IL12Rβ2 also impairs clonogenic growth of EVI1<sup>low</sup> MOLM-13, THP-1 or HL-60 AML cells. Collectively, we show that exogenous factors like TPO can increase the susceptibility for iKMT2A-MLLT3-driven HSC-originating Evi1<sup>+</sup> AML expressing stem cell genes linked to transformation maintenance of cell lines, and poor disease outcome of patients.</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

Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月19日

查看全文
  • Hugues-Étienne Châtel-Soulet,
  • Sabine Juge,
  • Ana Luisa Pereira,
  • Jonathan Seguin,
  • Athimed El Taher,
  • Federica Valigi,
  • Zivojin Jevtic,
  • Rathick Sivalingam,
  • Frederik Otzen Bagger,
  • Paul Büschl,
  • Marwa Almosailleakh,
  • Alexander Tzankov,
  • Wei Tong,
  • Mineo Kurokawa,
  • César Nombela Arrieta,
  • Juerg Schwaller

摘要

To address the cellular origin of ecotropic virus integration site 1 (EVI1)-expressing aggressive KMT2A-rearranged acute myeloid leukaemia (AML) we integrate an Evi1-GFP reporter allele in the inducible iKMT2A-MLLT3 mouse model. We observe that a single injection of thrombopoietin (TPO) selectively increases the number of cycling Evi1+ haematopoietic stem cells (HSC) and accelerates AML initiation. Comparison of mouse Evi1+ KMT2-MLLT3+ AML originating from TPO-stimulated HSC with human EVI1+AML reveals higher expression of HSC genes including IL12Rβ2 and INPP4B linked to poor disease outcome of patients of four large AML cohorts. Knockdown experiments show exclusive MECOM-dependency of human EVI1high KMT2A-rearranged OCI-AML4 cells while reduction of IL12Rβ2 also impairs clonogenic growth of EVI1low MOLM-13, THP-1 or HL-60 AML cells. Collectively, we show that exogenous factors like TPO can increase the susceptibility for iKMT2A-MLLT3-driven HSC-originating Evi1+ AML expressing stem cell genes linked to transformation maintenance of cell lines, and poor disease outcome of patients.