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PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia

Helen M. McRae, Alexandra L. Garnham, Yifang Hu, Matthew T. Witkowski, Mark A. Corbett, Mathew P. Dixon, Rose E. May, Bilal N. Sheikh, William Chiang, Andrew J. Kueh, Tan A. Nguyen, Kevin Man, Renee Gloury, Brandon J. Aubrey, Antonia Policheni, Ladina Di Rago, Warren S. Alexander, Daniel H.D. Gray, Andreas Strasser, Edwin D. Hawkins, Stephen Wilcox, Jozef Gécz, Axel Kallies, Matthew P. McCormack, Gordon K. Smyth, Anne K. Voss and Tim Thomas

Key points

  • PHF6 is a tumor suppressor and loss of PHF6 synergizes with ectopic TLX3 expression to cause rapid onset, fully penetrant leukemia.

  • Loss of PHF6 leads to sustained and robust HSC reconstitution beyond quaternary transplants and promotes progenitor production.

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.

  • Submitted July 2, 2018.
  • Accepted January 22, 2019.