PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia
- Author(s)
- McRae, HM; Garnham, AL; Hu, Y; Witkowski, MT; Corbett, MA; Dixon, MP; May, RE; Sheikh, BN; Chiang, W; Kueh, AJ; Nguyen, TA; Man, K; Gloury, R; Aubrey, BJ; Policheni, A; Di Rago, L; Alexander, WS; Gray, DHD; Strasser, A; Hawkins, ED; Wilcox, S; Gecz, J; Kallies, A; McCormack, MP; Smyth, GK; Voss, AK; Thomas, T;
- Journal Title
- Blood
- Publication Type
- Journal Article
- Abstract
- 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 yet 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, an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased, 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 alpha and beta 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 important for fine-tuning hematopoietic stem and progenitor cell homeostasis.
- Publisher
- ASH
- Research Division(s)
- Epigenetics And Development; Bioinformatics; Blood Cells And Blood Cancer; Inflammation; Immunology
- PubMed ID
- 30755422
- Publisher's Version
- https://doi.org/10.1182/blood-2018-07-860726
- NHMRC Grants
- NHMRC/1029481, NHMRC/1084248, NHMRC/1016701, NHMRC/1113577, NHMRC/1003435, NHMRC/575512, NHMRC/1081421, NHMRC/1020363, NHMRC/1058344,
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- Refer to copyright notice on published article.
Creation Date: 2019-03-13 11:54:12
Last Modified: 2019-03-13 02:19:48