Signal-transducing adapter protein-1 is required for maintenance of leukemic stem cells in CML.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Apoptosis
/ genetics
Cell Line, Tumor
Disease Models, Animal
Fusion Proteins, bcr-abl
/ genetics
Gene Expression Profiling
/ methods
Gene Expression Regulation, Leukemic
Humans
K562 Cells
Kaplan-Meier Estimate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
/ genetics
Mice, Inbred C57BL
Mice, Knockout
Neoplastic Stem Cells
/ metabolism
Protein Binding
Proto-Oncogene Proteins c-bcl-2
/ genetics
Signal Transduction
/ genetics
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
21
08
2019
accepted:
03
07
2020
revised:
12
06
2020
pubmed:
15
7
2020
medline:
1
12
2020
entrez:
15
7
2020
Statut:
ppublish
Résumé
The family of signal-transducing adapter proteins (STAPs) has been reported to be involved in a variety of intracellular signaling pathways and implicated as transcriptional factors. We previously cloned STAP-2 as a c-Fms interacting protein and explored its effects on chronic myeloid leukemia (CML) leukemogenesis. STAP-2 binds to BCR-ABL, upregulates BCR-ABL phosphorylation, and activates its downstream molecules. In this study, we evaluated the role of STAP-1, another member of the STAP family, in CML pathogenesis. We found that the expression of STAP-1 is aberrantly upregulated in CML stem cells (LSCs) in patients' bone marrow. Using experimental model mice, deletion of STAP-1 prolonged the survival of CML mice with inducing apoptosis of LSCs. The impaired phosphorylation status of STAT5 by STAP-1 ablation leads to downregulation of antiapoptotic genes, Bcl-2 and Bcl-xL. Interestingly, transcriptome analyses indicated that STAP-1 affects several signaling pathways related to BCR-ABL, JAK2, and PPARγ. This adapter protein directly binds to not only BCR-ABL, but also STAT5 proteins, showing synergistic effects of STAP-1 inhibition and BCR-ABL or JAK2 tyrosine kinase inhibition. Our results identified STAP-1 as a regulator of CML LSCs and suggested it to be a potential therapeutic target for CML.
Identifiants
pubmed: 32661325
doi: 10.1038/s41388-020-01387-9
pii: 10.1038/s41388-020-01387-9
pmc: PMC7441008
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
BCL2 protein, human
0
Proto-Oncogene Proteins c-bcl-2
0
STAP-1 protein, mouse
0
STAP1 protein, human
0
Fusion Proteins, bcr-abl
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5601-5615Références
Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5:172–83.
pubmed: 15719031
doi: 10.1038/nrc1567
Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 2009;113:1619–30.
pubmed: 18827185
pmcid: 3952549
doi: 10.1182/blood-2008-03-144790
Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35.
doi: 10.1016/S1470-2045(10)70233-3
pubmed: 20965785
Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122:515–22.
pubmed: 23704092
doi: 10.1182/blood-2013-02-483750
Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19:747–57.
doi: 10.1016/S1470-2045(18)30192-X
pubmed: 29735299
Graham SM, Jørgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319–25.
pubmed: 11756187
doi: 10.1182/blood.V99.1.319
Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107:4532–9.
doi: 10.1182/blood-2005-07-2947
pubmed: 16469872
Lemoli RM, Salvestrini V, Bianchi E, Bertolini F, Fogli M, Amabile M, et al. Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34- cell population with intrinsic resistance to imatinib. Blood. 2009;114:5191–200.
pubmed: 19855080
doi: 10.1182/blood-2008-08-176016
Chu S, McDonald T, Lin A, Chakraborty S, Huang Q, Snyder DS, et al. Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood. 2011;118:5565–72.
pubmed: 21931114
pmcid: 3217358
doi: 10.1182/blood-2010-12-327437
Chomel JC, Bonnet ML, Sorel N, Sloma I, Bennaceur-Griscelli A, Rea D, et al. Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation. Oncotarget. 2016;7:35293–301.
pubmed: 27167108
pmcid: 5085229
doi: 10.18632/oncotarget.9182
Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Bartley PA, et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia. 2010;24:1719–24.
pubmed: 20811403
doi: 10.1038/leu.2010.185
Giustacchini A, Thongjuea S, Barkas N, Woll PS, Povinelli BJ, Booth CAG, et al. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med. 2017;23:692–702.
doi: 10.1038/nm.4336
pubmed: 28504724
Warfvinge R, Geironson L, Sommarin MNE, Lang S, Karlsson C, Roschupkina T, et al. Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML. Blood. 2017;129:2384–94.
pubmed: 28122740
pmcid: 5484462
doi: 10.1182/blood-2016-07-728873
Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011;121:396–409.
doi: 10.1172/JCI35721
pubmed: 21157039
Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119:1501–10.
pubmed: 22184410
pmcid: 3286213
doi: 10.1182/blood-2010-12-326843
Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463:676–80.
pubmed: 20130650
doi: 10.1038/nature08734
Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528–41.
pubmed: 18068630
pmcid: 2262869
doi: 10.1016/j.ccr.2007.11.003
Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458:776–9.
pubmed: 19169242
pmcid: 2946231
doi: 10.1038/nature07737
Wang Y, Cai D, Brendel C, Barett C, Erben P, Manley PW, et al. Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood. 2007;109:2147–55.
pubmed: 17090651
doi: 10.1182/blood-2006-08-040022
Liu X, Rothe K, Yen R, Fruhstorfer C, Maetzig T, Chen M, et al. A novel AHI-1-BCR-ABL-DNM2 complex regulates leukemic properties of primitive CML cells through enhanced cellular endocytosis and ROS-mediated autophagy. Leukemia. 2017;31:2376–87.
pubmed: 28366933
pmcid: 5668499
doi: 10.1038/leu.2017.108
Gallipoli P, Cook A, Rhodes S, Hopcroft L, Wheadon H, Whetton AD, et al. JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood. 2014;124:1492–501.
pubmed: 24957147
pmcid: 4148771
doi: 10.1182/blood-2013-12-545640
Gallipoli P, Pellicano F, Morrison H, Laidlaw K, Allan EK, Bhatia R, et al. Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation. Blood. 2013;122:3335–9.
pubmed: 24041577
pmcid: 3953090
doi: 10.1182/blood-2013-02-485607
Ågerstam H, Hansen N, von Palffy S, Sandén C, Reckzeh K, Karlsson C, et al. IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models. Blood. 2016;128:2683–93.
pubmed: 27621309
doi: 10.1182/blood-2015-11-679985
Reynaud D, Pietras E, Barry-Holson K, Mir A, Binnewies M, Jeanne M, et al. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell. 2011;20:661–73.
pubmed: 22094259
pmcid: 3220886
doi: 10.1016/j.ccr.2011.10.012
Prost S, Relouzat F, Spentchian M, Ouzegdouh Y, Saliba J, Massonnet G, et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists. Nature. 2015;525:380–3.
doi: 10.1038/nature15248
pubmed: 26331539
Zhang B, Ho YW, Huang Q, Maeda T, Lin A, Lee SU, et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell. 2012;21:577–92.
pubmed: 22516264
pmcid: 3332001
doi: 10.1016/j.ccr.2012.02.018
Agarwal P, Isringhausen S, Li H, Paterson AJ, He J, Gomariz Á, et al. Mesenchymal niche-specific expression of Cxcl12 controls quiescence of treatment-resistant leukemia stem cells. Cell Stem Cell. 2019;24:769.
pubmed: 30905620
pmcid: 6499704
doi: 10.1016/j.stem.2019.02.018
Masuhara M, Nagao K, Nishikawa M, Sasaki M, Yoshimura A, Osawa M. Molecular cloning of murine STAP-1, the stem-cell-specific adaptor protein containing PH and SH2 domains. Biochem Biophys Res Commun. 2000;268:697–703.
pubmed: 10679268
doi: 10.1006/bbrc.2000.2223
Minoguchi M, Minoguchi S, Aki D, Joo A, Yamamoto T, Yumioka T, et al. STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif. J Biol Chem. 2003;278:11182–9.
pubmed: 12540842
doi: 10.1074/jbc.M211230200
Sekine Y, Yamamoto T, Yumioka T, Sugiyama K, Tsuji S, Oritani K, et al. Physical and functional interactions between STAP-2/BKS and STAT5. J Biol Chem. 2005;280:8188–96.
pubmed: 15611091
doi: 10.1074/jbc.M411692200
Ikeda O, Mizushima A, Sekine Y, Yamamoto C, Muromoto R, Nanbo A, et al. Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells. Cancer Sci. 2011;102:756–61.
pubmed: 21205088
doi: 10.1111/j.1349-7006.2010.01842.x
Sekine Y, Ikeda O, Mizushima A, Ueno Y, Muromoto R, Yoshimura A, et al. STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis. Oncogene. 2012;31:4384–96.
pubmed: 22231445
doi: 10.1038/onc.2011.604
Diaz-Blanco E, Bruns I, Neumann F, Fischer JC, Graef T, Rosskopf M, et al. Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase. Leukemia. 2007;21:494–504.
pubmed: 17252012
doi: 10.1038/sj.leu.2404549
Fujita N, Oritani K, Ichii M, Yokota T, Saitoh N, Okuzaki D, et al. Signal-transducing adaptor protein-2 regulates macrophage migration into inflammatory sites during dextran sodium sulfate induced colitis. Eur J Immunol. 2014;44:1791–801.
pubmed: 24733425
doi: 10.1002/eji.201344239
Abraham SA, Hopcroft LE, Carrick E, Drotar ME, Dunn K, Williamson AJ, et al. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature. 2016;534:341–6.
pubmed: 27281222
pmcid: 4913876
doi: 10.1038/nature18288
Zhang H, Li H, Xi HS, Li S. HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells. Blood. 2012;119:2595–607.
pubmed: 22275380
pmcid: 3311277
doi: 10.1182/blood-2011-10-387381
Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, et al. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med. 2011;208:2163–74.
pubmed: 21911423
pmcid: 3201200
doi: 10.1084/jem.20110304
Sweet K, Hazlehurst L, Sahakian E, Powers J, Nodzon L, Kayali F, et al. A phase I clinical trial of ruxolitinib in combination with nilotinib in chronic myeloid leukemia patients with molecular evidence of disease. Leuk Res. 2018;74:89–96.
pubmed: 30340199
pmcid: 7787269
doi: 10.1016/j.leukres.2018.10.002
Ohya K, Kajigaya S, Kitanaka A, Yoshida K, Miyazato A, Yamashita Y, et al. Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase. Proc Natl Acad Sci USA. 1999;96:11976–81.
pubmed: 10518561
doi: 10.1073/pnas.96.21.11976
pmcid: 18397
Mitchell PJ, Sara EA, Crompton MR. A novel adaptor-like protein which is a substrate for the non-receptor tyrosine kinase, BRK. Oncogene. 2000;19:4273–82.
pubmed: 10980601
doi: 10.1038/sj.onc.1203775
Stoecker K, Weigelt K, Ebert S, Karlstetter M, Walczak Y, Langmann T. Induction of STAP-1 promotes neurotoxic activation of microglia. Biochem Biophys Res Commun. 2009;379:121–6.
pubmed: 19100238
doi: 10.1016/j.bbrc.2008.12.021
Steeghs EMP, Bakker M, Hoogkamer AQ, Boer JM, Hartman QJ, Stalpers F, et al. High STAP1 expression in DUX4-rearranged cases is not suitable as therapeutic target in pediatric B-cell precursor acute lymphoblastic leukemia. Sci Rep. 2018;8:693.
pubmed: 29330417
pmcid: 5766593
doi: 10.1038/s41598-017-17704-4
Nieborowska-Skorska M, Wasik MA, Slupianek A, Salomoni P, Kitamura T, Calabretta B, et al. Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis. J Exp Med. 1999;189:1229–42.
pubmed: 10209040
pmcid: 2193033
doi: 10.1084/jem.189.8.1229
Sillaber C, Gesbert F, Frank DA, Sattler M, Griffin JD. STAT5 activation contributes to growth and viability in Bcr/Abl-transformed cells. Blood. 2000;95:2118–25.
pubmed: 10706883
doi: 10.1182/blood.V95.6.2118
Hoelbl A, Schuster C, Kovacic B, Zhu B, Wickre M, Hoelzl MA, et al. Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. EMBO Mol Med. 2010;2:98–110.
pubmed: 20201032
pmcid: 2906698
doi: 10.1002/emmm.201000062
Warsch W, Grundschober E, Berger A, Gille L, Cerny-Reiterer S, Tigan AS, et al. STAT5 triggers BCR-ABL1 mutation by mediating ROS production in chronic myeloid leukaemia. Oncotarget. 2012;3:1669–87.
pubmed: 23458731
pmcid: 3681503
doi: 10.18632/oncotarget.806
Nelson EA, Walker SR, Weisberg E, Bar-Natan M, Barrett R, Gashin LB, et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood. 2011;117:3421–9.
pubmed: 21233313
pmcid: 3069678
doi: 10.1182/blood-2009-11-255232
Jiang X, Ng E, Yip C, Eisterer W, Chalandon Y, Stuible M, et al. Primitive interleukin 3 null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo. Blood. 2002;100:3731–40.
pubmed: 12393460
doi: 10.1182/blood-2002-05-1324
Tokunaga M, Ezoe S, Tanaka H, Satoh Y, Fukushima K, Matsui K, et al. BCR-ABL but not JAK2 V617F inhibits erythropoiesis through the Ras signal by inducing p21CIP1/WAF1. J Biol Chem. 2010;285:31774–82.
pubmed: 20663870
pmcid: 2951249
doi: 10.1074/jbc.M110.118653
Uchida N, Nassehi T, Drysdale CM, Gamer J, Yapundich M, Demirci S, et al. High-efficiency lentiviral transduction of human CD34. Mol Ther Methods Clin Dev. 2019;13:187–96.
pubmed: 30788387
pmcid: 6370599
doi: 10.1016/j.omtm.2019.01.005