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

(2019) CANCER DISCOVERY. 9(3). p.436-451
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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. SIGNIFICANCE: Phf6 controls HSC homeostasis, leukemia initiation, and T-ALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of T-ALL.
Keywords
PROGNOSTIC RELEVANCE, CLONAL HEMATOPOIESIS, MUTATIONS, EXPRESSION, MECHANISMS, EVOLUTION, COMPLEX, NOTCH1, MICE, MYC

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MLA
Wendorff, Agnieszka A et al. “Phf6 Loss Enhances HSC Self-renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL.” CANCER DISCOVERY 9.3 (2019): 436–451. Print.
APA
Wendorff, A. A., Quinn, S. A., Rashkovan, M., Madubata, C. J., Ambesi-Impiombato, A., Litzow, M. R., Tallman, M. S., et al. (2019). Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-ALL. CANCER DISCOVERY, 9(3), 436–451.
Chicago author-date
Wendorff, Agnieszka A, S Aidan Quinn, Marissa Rashkovan, Chioma J Madubata, Alberto Ambesi-Impiombato, Mark R Litzow, Martin S Tallman, et al. 2019. “Phf6 Loss Enhances HSC Self-renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL.” Cancer Discovery 9 (3): 436–451.
Chicago author-date (all authors)
Wendorff, Agnieszka A, 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, and Adolfo A Ferrando. 2019. “Phf6 Loss Enhances HSC Self-renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL.” Cancer Discovery 9 (3): 436–451.
Vancouver
1.
Wendorff AA, Quinn SA, Rashkovan M, Madubata CJ, Ambesi-Impiombato A, Litzow MR, et al. Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-ALL. CANCER DISCOVERY. 2019;9(3):436–51.
IEEE
[1]
A. A. Wendorff et al., “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, 2019.
@article{8613048,
  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. 
SIGNIFICANCE: Phf6 controls HSC homeostasis, leukemia initiation, and T-ALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of T-ALL.},
  author       = {Wendorff, Agnieszka A and Quinn, S Aidan and Rashkovan, Marissa and Madubata, Chioma J and Ambesi-Impiombato, Alberto and Litzow, Mark R and Tallman, Martin S and Paietta, Elisabeth and Paganin, Maddalena and Basso, Giuseppe and Gastier-Foster, Julie M and Loh, Mignon L and Rabadan, Raul and Van Vlierberghe, Pieter and Ferrando, Adolfo A},
  issn         = {2159-8274},
  journal      = {CANCER DISCOVERY},
  keywords     = {PROGNOSTIC RELEVANCE,CLONAL HEMATOPOIESIS,MUTATIONS,EXPRESSION,MECHANISMS,EVOLUTION,COMPLEX,NOTCH1,MICE,MYC},
  language     = {eng},
  number       = {3},
  pages        = {436--451},
  title        = {Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-ALL},
  url          = {http://dx.doi.org/10.1158/2159-8290.cd-18-1005},
  volume       = {9},
  year         = {2019},
}

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