Knock-out of Hopx disrupts stemness and quiescence of hematopoietic stem cells in mice.
Chien-Chin LinChi-Yuan YaoYueh-Chwen HsuHsin-An HouChang-Tsu YuanYi-Hung LiChein-Jun KaoPo-Han ChuangYu-Chiao ChiuYidong ChenWen-Chien ChouHwei-Fang TienPublished in: Oncogene (2020)
HOPX is a stem cell marker in hair follicles and intestines. It was shown critical for primitive hematopoiesis. We previously showed an association between higher HOPX expression and clinical characteristics related to stemness and quiescence of leukemic cells in acute myeloid leukemia (AML) patients. To further explore its physiologic functions in hematopoietic system, we generated a mouse model with hematopoietic cell-specific knockout of Hopx (Hopx-/-). In young Hopx-/- mice, the hematopoietic stem cells (HSC) showed decreased reconstitution ability after serial transplantation. Further transcriptomic study revealed decreased HSC signatures in long-term HSCs from the Hopx-/- mice. At 18 months of age, half of the Hopx-/- mice developed cytopenia and splenomegaly. Bone marrow (BM) from the sick mice showed myeloid hyperplasia with predominant mature neutrophils, and decreased progenitor cells and lymphocytes. These phenotypes suggested critical functions of Hopx in maintaining HSC quiescence. Transcriptomic study of the Hopx-/- marrow cells showed significant downregulation of the Cxcl12-Cxcr4 axis, which is critical for maintenance of HSC quiescence. We next examined the role of Hopx in AML by using the MN1 overexpression murine leukemia model. Mice transplanted with MN1-overexpressed Hopx-/- BM cells developed AML with more aggressive phenotypes compared with those transplanted with MN1-overexpressed Hopx-wild cells. Hopx-/- MN1-overexpressed leukemia cells showed higher proliferation rate and downregulation of Cxcl12 and Cxcr4. Furthermore, in human AML, BM plasma CXCL12 levels were lower in patients with lower HOPX expression. In conclusion, our study highlights the roles of Hopx in maintenance of quiescence of the hematopoietic stem cells through CXCL12 pathway in vivo and provides implication of this protein in normal and malignant hematopoiesis.
Keyphrases
- stem cells
- bone marrow
- induced apoptosis
- acute myeloid leukemia
- cell cycle arrest
- high fat diet induced
- mouse model
- cell therapy
- signaling pathway
- cell proliferation
- single cell
- oxidative stress
- poor prognosis
- newly diagnosed
- type diabetes
- dna methylation
- insulin resistance
- allogeneic hematopoietic stem cell transplantation
- transcription factor
- epithelial mesenchymal transition
- end stage renal disease
- metabolic syndrome
- immune response
- room temperature
- pi k akt
- skeletal muscle
- rna seq
- peritoneal dialysis
- metal organic framework
- long non coding rna
- protein protein