Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-ALL Journal Article
| Authors: | 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. |
| Article 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. © 2018 American Association for Cancer Research. |
| Keywords: | signal transduction; controlled study; human tissue; protein expression; unclassified drug; gene mutation; gene deletion; histopathology; fluorouracil; nonhuman; flow cytometry; animal cell; mouse; animal tissue; dna damage; gene; cell cycle; microrna; gene expression; tumor volume; animal experiment; animal model; genotype; cyclophosphamide; immunofluorescence; acute lymphoblastic leukemia; western blotting; cell isolation; remission; single drug dose; tamoxifen; down regulation; upregulation; hematopoietic stem cell; homeostasis; bone marrow transplantation; cell suspension; granulocyte colony stimulating factor; cell activity; t lymphocyte activation; cell selection; notch1 receptor; rna sequence; human; male; female; article; stem cell self-renewal; whole exome sequencing; gene knockout; plant homeodomain 6 gene; sigma aldrich |
| Journal Title: | Cancer Discovery |
| Volume: | 9 |
| Issue: | 3 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-03-01 |
| Start Page: | 436 |
| End Page: | 451 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-18-1005 |
| PUBMED: | 30567843 |
| PROVIDER: | scopus |
| PMCID: | PMC6425751 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2019 -- Source: Scopus |
