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 & 7 others Stephen Wilcox, Jozef Gécz, Axel Kallies, Matthew P. McCormack, Gordon K. Smyth, Anne K. Voss, Tim Thomas

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4 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1729-1741
Number of pages13
JournalBlood
Volume133
Issue number16
DOIs
Publication statusPublished - 18 Apr 2019

Cite this

McRae, H. M., Garnham, A. L., Hu, Y., Witkowski, M. T., Corbett, M. A., Dixon, M. P., ... Thomas, T. (2019). PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia. Blood, 133(16), 1729-1741. https://doi.org/10.1182/blood-2018-07-860726
McRae, Helen M. ; Garnham, Alexandra L. ; Hu, Yifang ; Witkowski, Matthew T. ; Corbett, Mark A. ; Dixon, Mathew P. ; May, Rose E. ; Sheikh, Bilal N. ; Chiang, William ; Kueh, Andrew J. ; Nguyen, Tan A. ; Man, Kevin ; Gloury, Renee ; Aubrey, Brandon J. ; Policheni, Antonia ; Di Rago, Ladina ; Alexander, Warren S. ; Gray, Daniel H.D. ; Strasser, Andreas ; Hawkins, Edwin D. ; Wilcox, Stephen ; Gécz, Jozef ; Kallies, Axel ; McCormack, Matthew P. ; Smyth, Gordon K. ; Voss, Anne K. ; Thomas, Tim. / PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia. In: Blood. 2019 ; Vol. 133, No. 16. pp. 1729-1741.
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title = "PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia",
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 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.",
author = "McRae, {Helen M.} and Garnham, {Alexandra L.} and Yifang Hu and Witkowski, {Matthew T.} and Corbett, {Mark A.} and Dixon, {Mathew P.} and May, {Rose E.} and Sheikh, {Bilal N.} and William Chiang and Kueh, {Andrew J.} and Nguyen, {Tan A.} and Kevin Man and Renee Gloury and Aubrey, {Brandon J.} and Antonia Policheni and {Di Rago}, Ladina and Alexander, {Warren S.} and Gray, {Daniel H.D.} and Andreas Strasser and Hawkins, {Edwin D.} and Stephen Wilcox and Jozef G{\'e}cz and Axel Kallies and McCormack, {Matthew P.} and Smyth, {Gordon K.} and Voss, {Anne K.} and Tim Thomas",
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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, Gécz, J, Kallies, A, McCormack, MP, Smyth, GK, Voss, AK & Thomas, T 2019, 'PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia', Blood, vol. 133, no. 16, pp. 1729-1741. https://doi.org/10.1182/blood-2018-07-860726

PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia. / McRae, Helen M.; Garnham, Alexandra L.; Hu, Yifang; Witkowski, Matthew T.; Corbett, Mark A.; Dixon, Mathew P.; May, Rose E.; Sheikh, Bilal N.; Chiang, William; Kueh, Andrew J.; Nguyen, Tan A.; Man, Kevin; Gloury, Renee; Aubrey, Brandon J.; Policheni, Antonia; Di Rago, Ladina; Alexander, Warren S.; Gray, Daniel H.D.; Strasser, Andreas; Hawkins, Edwin D.; Wilcox, Stephen; Gécz, Jozef; Kallies, Axel; McCormack, Matthew P.; Smyth, Gordon K.; Voss, Anne K.; Thomas, Tim.

In: Blood, Vol. 133, No. 16, 18.04.2019, p. 1729-1741.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia

AU - McRae, Helen M.

AU - Garnham, Alexandra L.

AU - Hu, Yifang

AU - Witkowski, Matthew T.

AU - Corbett, Mark A.

AU - Dixon, Mathew P.

AU - May, Rose E.

AU - Sheikh, Bilal N.

AU - Chiang, William

AU - Kueh, Andrew J.

AU - Nguyen, Tan A.

AU - Man, Kevin

AU - Gloury, Renee

AU - Aubrey, Brandon J.

AU - Policheni, Antonia

AU - Di Rago, Ladina

AU - Alexander, Warren S.

AU - Gray, Daniel H.D.

AU - Strasser, Andreas

AU - Hawkins, Edwin D.

AU - Wilcox, Stephen

AU - Gécz, Jozef

AU - Kallies, Axel

AU - McCormack, Matthew P.

AU - Smyth, Gordon K.

AU - Voss, Anne K.

AU - Thomas, Tim

PY - 2019/4/18

Y1 - 2019/4/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85065011999&partnerID=8YFLogxK

U2 - 10.1182/blood-2018-07-860726

DO - 10.1182/blood-2018-07-860726

M3 - Article

VL - 133

SP - 1729

EP - 1741

JO - Blood

JF - Blood

SN - 0006-4971

IS - 16

ER -