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<p>Apolipoprotein C2 (APOC2) has been identified as a potential therapeutic target for acute myeloid leukemia, but its impact on normal hematopoiesis remains unclear. Here we generated a global inducible <i>Apoc2</i> knockout (KO) mouse model by breeding <i>R26-CreERT2</i> mice with mice homozygous for <i>Apoc2</i> <i>lox</i> sites (<i>Apoc2</i><sup><i>fl/fl</i></sup>) over three generations. Global <i>Apoc2</i> KO was induced in 4–8-week-old mice by 5 consecutive days of intraperitoneal administration of tamoxifen. Successful <i>Apoc2</i> KO was confirmed by measuring <i>Apoc2</i> mRNA levels, showing 80–99% reduction in the liver, bone marrow, spleen and blood tissues compared with wild type (WT). Despite significantly higher serum triglyceride levels in the <i>Apoc2-</i>KO group, no apparent abnormal phenotypes were observed. In vitro expansion of the hematopoietic stem and progenitor cells and splenocytes from <i>Apoc2</i>-KO were comparable to that of WT mice. In addition, <i>Apoc2</i> deletion did not significantly affect the colony-forming ability or the competitive repopulation ability of hematopoietic stem and progenitor cells. Hematological analysis revealed no significant differences between <i>Apoc2-</i>KO and WT mice. RNA-sequencing analysis of bone marrow samples from the <i>Apoc2-</i>KO group identified four significantly downregulated genes and five upregulated genes, including <i>Gm16867</i>, which is orthologous to the human <i>SLC25A37</i> gene involved in mitochondrial iron homeostasis. Gene set enrichment analysis revealed the enrichment of heme metabolism (false discovery rate 0.077). Our study demonstrates that deletion of <i>Apoc2</i> exhibits limited impact on normal hematopoiesis under normal conditions. Future characterization of this Cre-inducible <i>Apoc2</i>-KO mice under stress conditions or during aging is needed to fully demonstrate the biological impact of <i>Apoc2</i> deletion.</p>

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Establishment and functional analysis of an inducible Apoc2-knockout mouse model to investigate the role of Apoc2 in normal hematopoiesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Xiaochen Zhang,
  • Ritu Chandwani,
  • Mateusz Pospiech,
  • Yiting Meng,
  • Kanaka Dhuri,
  • Atham Ali,
  • Bhakti Thakker,
  • Shephali Milind Kadam,
  • Wenda Zhu,
  • Yiyu Xiao,
  • Denis Sviridov,
  • Anna Wolska,
  • Alan T. Remaley,
  • Houda Alachkar

摘要

Apolipoprotein C2 (APOC2) has been identified as a potential therapeutic target for acute myeloid leukemia, but its impact on normal hematopoiesis remains unclear. Here we generated a global inducible Apoc2 knockout (KO) mouse model by breeding R26-CreERT2 mice with mice homozygous for Apoc2 lox sites (Apoc2fl/fl) over three generations. Global Apoc2 KO was induced in 4–8-week-old mice by 5 consecutive days of intraperitoneal administration of tamoxifen. Successful Apoc2 KO was confirmed by measuring Apoc2 mRNA levels, showing 80–99% reduction in the liver, bone marrow, spleen and blood tissues compared with wild type (WT). Despite significantly higher serum triglyceride levels in the Apoc2-KO group, no apparent abnormal phenotypes were observed. In vitro expansion of the hematopoietic stem and progenitor cells and splenocytes from Apoc2-KO were comparable to that of WT mice. In addition, Apoc2 deletion did not significantly affect the colony-forming ability or the competitive repopulation ability of hematopoietic stem and progenitor cells. Hematological analysis revealed no significant differences between Apoc2-KO and WT mice. RNA-sequencing analysis of bone marrow samples from the Apoc2-KO group identified four significantly downregulated genes and five upregulated genes, including Gm16867, which is orthologous to the human SLC25A37 gene involved in mitochondrial iron homeostasis. Gene set enrichment analysis revealed the enrichment of heme metabolism (false discovery rate 0.077). Our study demonstrates that deletion of Apoc2 exhibits limited impact on normal hematopoiesis under normal conditions. Future characterization of this Cre-inducible Apoc2-KO mice under stress conditions or during aging is needed to fully demonstrate the biological impact of Apoc2 deletion.