Prdm3 and Prdm16 cooperatively maintain hematopoiesis and clonogenic potential
| Autor: | Archibald S. Perkins, Kelly A. McGlynn, Alin Vonica, Sarah Rudzinskas, Yi Zhang, Rongli Sun |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Cell division Cell Survival Apoptosis Biology Models Biological Cell Line 03 medical and health sciences Mice 0302 clinical medicine Genetics medicine Animals Granulocyte Precursor Cells Progenitor cell Molecular Biology Mice Knockout Bone marrow failure Hematopoietic stem cell Cell Biology Hematology medicine.disease MDS1 and EVI1 Complex Locus Protein Cell biology Hematopoiesis DNA-Binding Proteins Haematopoiesis 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Knockout mouse Bone marrow Stem cell Transcription Factors |
| Zdroj: | Experimental hematology. 85 |
| ISSN: | 1873-2399 |
| Popis: | Mds1-Evi1 (also known as Prdm3) and Prdm16 are two highly related zinc finger transcription factors that, within the hematopoietic system, are both expressed primarily in hematopoietic stem cells (HSCs). Our laboratory previously found that constitutive Mds1-Evi1 knockout mice are viable, but their HSCs are unable to withstand myeloablative chemotherapy or effectively transplant irradiated recipient mice. A similar phenotype has been observed for Prdm16, except that the Prdm16 constitutive knockout is lethal. Here, we created a novel double-knockout model of Mds1-Evi1 and Prdm16 in the bone marrow, in which double knockout occurs only in cells that endogenously express Mds1-Evi1 and only upon induction with tamoxifen. We show that combined Mds1-Evi1/Prdm16 deficiency causes bone marrow failure within 15 days, with rapid loss in all progenitor compartments, while the peripheral blood exhibits progressive reductions in peripheral monocytes and granulocytes. We found that surviving hematopoietic stem cells and granulocytic progenitors had elevated apoptosis and cell division, and were unable to form colonies in vitro; adding back wild-type Mds1-Evi1 or Prdm16 to double-knockout bone marrow restores colony formation, and for MDS1-EVI1, this activity depends on a functional PR domain. All of these phenotypic effects were exhibited at milder levels in Mds1-Evi1 and Prdm16 single-knockout controls. Overall, these results illustrate that Mds1-Evi1 and Prdm16 play additive roles in maintaining normal hematopoietic stem cell survival. |
| Databáze: | OpenAIRE |
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