PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia
| Autor: | Andreas Strasser, William Chiang, Brandon J. Aubrey, Antonia N. Policheni, Mathew P. Dixon, Alexandra L. Garnham, Jozef Gecz, Matthew P. McCormack, Anne K. Voss, Axel Kallies, Kevin Man, Yifang Hu, Andrew J. Kueh, Tim Thomas, Stephen Wilcox, Daniel H.D. Gray, Renee Gloury, Tan A. Nguyen, Gordon K. Smyth, Helen M. McRae, Rose E. May, Edwin D. Hawkins, Ladina Di Rago, Bilal N. Sheikh, Matthew T. Witkowski, Warren S. Alexander, Mark A. Corbett |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Carcinogenesis
Hematopoiesis and Stem Cells Hematopoietic System Immunology Biology medicine.disease_cause Biochemistry Mice medicine Animals Humans Progenitor cell Receptors Interferon Regulation of gene expression Homeodomain Proteins Mice Knockout Leukemia Tumor Suppressor Proteins Hematopoietic Stem Cell Transplantation food and beverages Cell Biology Hematology medicine.disease Hematopoietic Stem Cells Transplantation Repressor Proteins Haematopoiesis Gene Expression Regulation Cancer research Ectopic expression Stem cell Carrier Proteins BLOOD Commentary |
| Popis: | Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and β receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukemia. Our data suggest that PHF6 is a hematopoietic tumor suppressor and is important for fine-tuning hematopoietic stem and progenitor cell homeostasis. |
| Databáze: | OpenAIRE |
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