Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All

Agnieszka A. Wendorff; S. Aidan Quinn; Marissa Rashkovan; Chioma J. Madubata; Alberto Ambesi-Impiombato; Mark R. Litzow; Martin S. Tallman; Elisabeth Paietta; Maddalena Paganin; Giuseppe Basso; Julie M. Gastier-Foster; Mignon L. Loh; Raul Rabadan; Pieter Van Vlierberghe; Adolfo A. Ferrando

doi:10.1158/2159-8290.CD-18-1005

Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All

Agnieszka A. Wendorff, S. Aidan Quinn, Marissa Rashkovan, Chioma J. Madubata, Alberto Ambesi-Impiombato, Mark R. Litzow, Martin S. Tallman, Elisabeth Paietta, Maddalena Paganin, Giuseppe Basso, Julie M. Gastier-Foster, Mignon L. Loh, Raul Rabadan, Pieter Van Vlierberghe, Adolfo A. Ferrando^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

Abstract

The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.

Original language	English (US)
Pages (from-to)	436-451
Number of pages	16
Journal	Cancer discovery
Volume	9
Issue number	3
DOIs	https://doi.org/10.1158/2159-8290.CD-18-1005
State	Published - Mar 1 2019

Funding

This work was supported by the NIH grants R35 CA210065 (A.A. Ferrando), R01 CA155743 (A.A. Ferrando), CA180827 (E. Paietta), CA196172 (E. Paietta), U54 CA193313 (R. Rabadan), R01 CA185486 (R. Rabadan), U54 CA209997 (R. Rabadan), CA180820 (ECOG-ACRIN), CA189859 (ECOG-ACRIN), CA14958 (ECOG-ACRIN), CA180791 (ECOG-ACRIN), CA17145 (ECOG-ACRIN), U10 CA180827 (ECOG-ACRIN), U10 CA98543 (J.M. Gastier-Foster and M.L. Loh); the Human Specimen Banking Grant U24 CA114766 (J.M. Gastier-Foster), and P30 CA013696 (in support of the Herbert Irving Comprehensive Cancer Center Genomics, Flow Cytometry and Transgenic Mouse Shared Resources). A.A. Wendorff was supported by a Rally Foundation fellowship. P. Van Vlierberghe was supported by the Fund for Scientific Research (FWO) Flanders (postdoctoral fellowship and Odysseus type 2 grant). M. Rashkovan was supported by a Damon-Runyon Sohn Pediatric Cancer fellowship. We are grateful to T. Ludwig (The Ohio State University Comprehensive Cancer Center) for the Rosa26+/Cre-ERT2 mouse. We thank E. Passegué for insightful suggestions in the experimental design and interpretation of our results. J.M. Gastier-Foster reports receiving commercial research grants from Bristol-Myers Squibb and Incyte Corporation. M.L. Loh is a consultant/advisory board member for Medisix Therapeutics. R. Rabadan is a consultant/advisory board member for CNIO. No potential conflicts of interest were disclosed by the other authors.

ASJC Scopus subject areas

Oncology

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Wendorff, A. A., Quinn, S. A., Rashkovan, M., Madubata, C. J., Ambesi-Impiombato, A., Litzow, M. R., Tallman, M. S., Paietta, E., Paganin, M., Basso, G., Gastier-Foster, J. M., Loh, M. L., Rabadan, R., Vlierberghe, P. V., & Ferrando, A. A. (2019). Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All. Cancer discovery, 9(3), 436-451. https://doi.org/10.1158/2159-8290.CD-18-1005

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title = "Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All",

abstract = "The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.",

author = "Wendorff, {Agnieszka A.} and Quinn, {S. Aidan} and Marissa Rashkovan and Madubata, {Chioma J.} and Alberto Ambesi-Impiombato and Litzow, {Mark R.} and Tallman, {Martin S.} and Elisabeth Paietta and Maddalena Paganin and Giuseppe Basso and Gastier-Foster, {Julie M.} and Loh, {Mignon L.} and Raul Rabadan and Vlierberghe, {Pieter Van} and Ferrando, {Adolfo A.}",

note = "Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2019",

month = mar,

day = "1",

doi = "10.1158/2159-8290.CD-18-1005",

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Wendorff, AA, Quinn, SA, Rashkovan, M, Madubata, CJ, Ambesi-Impiombato, A, Litzow, MR, Tallman, MS, Paietta, E, Paganin, M, Basso, G, Gastier-Foster, JM, Loh, ML, Rabadan, R, Vlierberghe, PV & Ferrando, AA 2019, 'Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All', Cancer discovery, vol. 9, no. 3, pp. 436-451. https://doi.org/10.1158/2159-8290.CD-18-1005

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T1 - Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All

AU - Wendorff, Agnieszka A.

AU - Quinn, S. Aidan

AU - Rashkovan, Marissa

AU - Madubata, Chioma J.

AU - Ambesi-Impiombato, Alberto

AU - Litzow, Mark R.

AU - Tallman, Martin S.

AU - Paietta, Elisabeth

AU - Paganin, Maddalena

AU - Basso, Giuseppe

AU - Gastier-Foster, Julie M.

AU - Loh, Mignon L.

AU - Rabadan, Raul

AU - Vlierberghe, Pieter Van

AU - Ferrando, Adolfo A.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.

AB - The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.

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Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All

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