title: SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells.
abstract: The FLT3-ITD mutation is frequently observed in acute myeloid leukemia (AML) and is associated with poor prognosis. In such patients, FLT3 tyrosine kinase inhibitors (TKIs) are only partially effective and do not eliminate the leukemia stem cells (LSCs) that are assumed to be the source of treatment failure. Here, we show that the NAD-dependent SIRT1 deacetylase is selectively overexpressed in primary human FLT3-ITD AML LSCs. This SIRT1 overexpression is related to enhanced expression of the USP22 deubiquitinase induced by c-MYC, leading to reduced SIRT1 ubiquitination and enhanced stability. Inhibition of SIRT1 expression or activity reduced the growth of FLT3-ITD AML LSCs and significantly enhanced TKI-mediated killing of the cells. Therefore, these results identify a c-MYC-related network that enhances SIRT1 protein expression in human FLT3-ITD AML LSCs and contributes to their maintenance. Inhibition of this oncogenic network could be an attractive approach for targeting FLT3-ITD AML LSCs to improve treatment outcomes.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Clinical Science, Hematology Section, University of Bergen, Bergen 5021, Norway.
authors.forename: Tereza
authors.initials: T
authors.lastname: Osdal
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Yinwei
authors.initials: Y
authors.lastname: Ho
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Chun
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Tinisha
authors.initials: T
authors.lastname: McDonald
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Puneet
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Lin
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Chu
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Yao-Te
authors.initials: YT
authors.lastname: Hsieh
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Cedric
authors.initials: C
authors.lastname: Dos Santos
authors.affiliation: Department of Cancer Biology, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Clinical Science, Hematology Section, University of Bergen, Bergen 5021, Norway.
authors.forename: Trung-Quang
authors.initials: TQ
authors.lastname: Ha
authors.affiliation: KinN Therapeutics AS, Bergen 5008, Norway.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Popa
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway.
authors.forename: Randi
authors.initials: R
authors.lastname: Hovland
authors.affiliation: Department of Clinical Science, Hematology Section, University of Bergen, Bergen 5021, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen 5021, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
authors.affiliation: Department of Clinical Science, Hematology Section, University of Bergen, Bergen 5021, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen 5021, Norway.
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Ya-Huei
authors.initials: YH
authors.lastname: Kuo
authors.affiliation: Department of Cancer Biology, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Wenyong
authors.initials: W
authors.lastname: Chen
authors.affiliation: Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Sonia
authors.initials: S
authors.lastname: Lain
authors.affiliation: Department of Clinical Science, Hematology Section, University of Bergen, Bergen 5021, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen 5021, Norway. Electronic address: emmet.mc.cormack@k2.uib.no.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address: rbhatia@coh.org.
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D052160:Benzothiazoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D020440:Gene Duplication / Q000187:drug effects; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; D052160:Benzothiazoles; D010671:Phenylurea Compounds; D016271:Proto-Oncogene Proteins c-myc; C544967:quizartinib; D051941:fms-Like Tyrosine Kinase 3; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; C527170:Usp22 protein, human; D056564:Sirtuin 1