FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
26
05
2023
accepted:
31
08
2023
revised:
18
08
2023
medline:
6
11
2023
pubmed:
10
9
2023
entrez:
9
9
2023
Statut:
ppublish
Résumé
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid blasts in the bone marrow (BM). Despite advances in therapy, the prognosis for AML patients remains poor, and there is a need to identify novel molecular pathways regulating tumor cell survival and proliferation. F-box ubiquitin E3 ligase, FBXO21, has low expression in AML, but expression correlates with survival in AML patients and patients with higher expression have poorer outcomes. Silencing FBXO21 in human-derived AML cell lines and primary patient samples leads to differentiation, inhibition of tumor progression, and sensitization to chemotherapy agents. Additionally, knockdown of FBXO21 leads to up-regulation of cytokine signaling pathways. Through a mass spectrometry-based proteomic analysis of FBXO21 in AML, we identified that FBXO21 ubiquitylates p85α, a regulatory subunit of the phosphoinositide 3-kinase (PI3K) pathway, for degradation resulting in decreased PI3K signaling, dimerization of free p85α and ERK activation. These findings reveal the ubiquitin E3 ligase, FBXO21, plays a critical role in regulating AML pathogenesis, specifically through alterations in PI3K via regulation of p85α protein stability.
Identifiants
pubmed: 37689825
doi: 10.1038/s41375-023-02020-w
pii: 10.1038/s41375-023-02020-w
pmc: PMC10624613
doi:
Substances chimiques
F-Box Proteins
0
FBXO21 protein, human
0
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Ubiquitin-Protein Ligases
EC 2.3.2.27
Ubiquitins
0
PIK3R1 protein, human
EC 2.7.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2197-2208Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM121316
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA262635
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI153090
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA042014
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK106829
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
King B, Trimarchi T, Reavie L, Xu L, Mullenders J, Ntziachristos P, et al. The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell. 2013;153:1552–66.
doi: 10.1016/j.cell.2013.05.041
pubmed: 23791182
pmcid: 4146439
Reavie L, Buckley SM, Loizou E, Takeishi S, Aranda-Orgilles B, Ndiaye-Lobry D, et al. Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell. 2013;23:362–75.
doi: 10.1016/j.ccr.2013.01.025
pubmed: 23518350
pmcid: 3609428
Cardozo T, Pagano M. The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol. 2004;5:739–51.
doi: 10.1038/nrm1471
pubmed: 15340381
Kipreos ET, Pagano M. The F-box protein family. Genome Biol. 2000;1:REVIEWS3002.
doi: 10.1186/gb-2000-1-5-reviews3002
pubmed: 11178263
pmcid: 138887
Hynes-Smith RW, Wittorf KJ, Buckley SM. Regulation of normal and malignant hematopoiesis by FBOX ubiquitin E3 ligases. Trends Immunol. 2020;41:1128–40.
doi: 10.1016/j.it.2020.10.003
pubmed: 33160841
pmcid: 7704775
Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.
doi: 10.1056/NEJMoa1301689
Watanabe K, Yumimoto K, Nakayama KI. FBXO21 mediates the ubiquitylation and proteasomal degradation of EID1. Genes Cells Devoted Mol Cell Mech. 2015;20:667–74.
doi: 10.1111/gtc.12260
Yoshida Y, Saeki Y, Murakami A, Kawawaki J, Tsuchiya H, Yoshihara H, et al. A comprehensive method for detecting ubiquitinated substrates using TR-TUBE. Proc Natl Acad Sci USA 2015;112:4630–5.
doi: 10.1073/pnas.1422313112
pubmed: 25827227
pmcid: 4403176
Zhang C, Li X, Adelmant G, Dobbins J, Geisen C, Oser MG, et al. Peptidic degron in EID1 is recognized by an SCF E3 ligase complex containing the orphan F-box protein FBXO21. Proc Natl Acad Sci USA 2015;112:15372–7.
doi: 10.1073/pnas.1522006112
pubmed: 26631746
pmcid: 4687553
Yu Z, Chen T, Li X, Yang M, Tang S, Zhu X, et al. Lys29-linkage of ASK1 by Skp1-cullin 1-Fbxo21 ubiquitin ligase complex is required for antiviral innate response. Elife. 2016;5:e14087.
Ye B, Dai Z, Liu B, Wang R, Li C, Huang G, et al. Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of EID1 stability. Stem Cells. 2014;32:623–35.
doi: 10.1002/stem.1580
pubmed: 24167073
Randle SJ, Laman H. F-box protein interactions with the hallmark pathways in cancer. Semin Cancer Biol. 2016;36:3–17.
doi: 10.1016/j.semcancer.2015.09.013
pubmed: 26416465
Wittorf KJ, Weber KK, Swenson SA, Buckley SM. Ubiquitin E3 ligase FBXO21 regulates cytokine-mediated signaling pathways, but is dispensable for steady-state hematopoiesis. Exp Hematol. 2022;114:33–42.e33.
doi: 10.1016/j.exphem.2022.08.002
pubmed: 35987460
Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Bene MC, et al. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol. 2010;28:2529–37.
doi: 10.1200/JCO.2009.23.4732
pubmed: 20406941
pmcid: 5569671
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.
doi: 10.1182/blood-2014-01-552984
pubmed: 24744269
pmcid: 4047501
Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74.
doi: 10.1182/blood-2009-07-235358
pubmed: 19880497
Gupta V, Tallman MS, Weisdorf DJ. Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood. 2011;117:2307–18.
doi: 10.1182/blood-2010-10-265603
pubmed: 21098397
Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014;32:3249–56.
doi: 10.1200/JCO.2013.53.8157
pubmed: 25154831
pmcid: 4178523
Liu M, Guo S, Stiles JK. The emerging role of CXCL10 in cancer (Review). Oncol Lett. 2011;2:583–9.
doi: 10.3892/ol.2011.300
pubmed: 22848232
pmcid: 3406435
Lunghi P, Tabilio A, Dall’Aglio PP, Ridolo E, Carlo-Stella C, Pelicci PG, et al. Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia. 2003;17:1783–93.
doi: 10.1038/sj.leu.2403032
pubmed: 12970778
Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood. 2003;102:972–80.
doi: 10.1182/blood-2002-11-3429
pubmed: 12702506
Hemmati S, Sinclair T, Tong M, Bartholdy B, Okabe RO, Ames K, et al. PI3 kinase alpha and delta promote hematopoietic stem cell activation. JCI Insight. 2019;5:pii:125832.
Ito Y, Hart JR, Ueno L, Vogt PK. Oncogenic activity of the regulatory subunit p85β of phosphatidylinositol 3-kinase (PI3K). Proc Natl Acad Sci USA 2014;111:16826–9.
doi: 10.1073/pnas.1420281111
pubmed: 25385636
pmcid: 4250105
Liu Y, Wang D, Li Z, Li X, Jin M, Jia N, et al. Pan-cancer analysis on the role of PIK3R1 and PIK3R2 in human tumors. Sci Rep. 2022;12:5924.
doi: 10.1038/s41598-022-09889-0
pubmed: 35395865
pmcid: 8993854
Fox M, Mott HR, Owen D. Class IA PI3K regulatory subunits: p110-independent roles and structures. Biochem Soc Trans. 2020;48:1397–417.
doi: 10.1042/BST20190845
pubmed: 32677674
pmcid: 7458397
Li X, Mak VCY, Zhou Y, Wang C, Wong ESY, Sharma R, et al. Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer. Nat Commun. 2019;10:716.
doi: 10.1038/s41467-019-08574-7
pubmed: 30755611
pmcid: 6372715
Hsu J-H, Shi Y, Frost P, Yan H, Hoang B, Sharma S, et al. Interleukin-6 activates phosphoinositol-3′ kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways. Oncogene. 2004;23:3368–75.
doi: 10.1038/sj.onc.1207459
pubmed: 15021914
Zhou C, Du J, Zhao L, Liu W, Zhao T, Liang H, et al. GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia. Cell Death Dis. 2021;12:231.
doi: 10.1038/s41419-021-03504-2
pubmed: 33658491
pmcid: 7930050
Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC, Kahn CR. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol. 2002;22:965–77.
doi: 10.1128/MCB.22.3.965-977.2002
pubmed: 11784871
pmcid: 133541
Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1:170–85.
doi: 10.1158/2159-8290.CD-11-0039
pubmed: 21984976
pmcid: 3187555
Cheung LW, Yu S, Zhang D, Li J, Ng PK, Panupinthu N, et al. Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer Cell. 2014;26:479–94.
doi: 10.1016/j.ccell.2014.08.017
pubmed: 25284480
pmcid: 4198486
Meyer C, Burmeister T, Gröger D, Tsaur G, Fechina L, Renneville A, et al. The MLL recombinome of acute leukemias in 2017. Leukemia. 2018;32:273–84. 2018/02/01
doi: 10.1038/leu.2017.213
pubmed: 28701730
Mrozek K, Bloomfield CD. Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. Hematol Am Soc Hematol Educ Program. 2006: 169–77.
Dimartino JF, Cleary ML. Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. Br J Haematol. 1999;106:614–26.
doi: 10.1046/j.1365-2141.1999.01439.x
pubmed: 10468849
Kamezaki K, Shimoda K, Numata A, Haro T, Kakumitsu H, Yoshie M, et al. Roles of Stat3 and ERK in G-CSF signaling. Stem Cells. 2005;23:252–63.
doi: 10.1634/stemcells.2004-0173a
pubmed: 15671148
Kurosawa M, Numazawa S, Tani Y, Yoshida T. ERK signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells. Am J Physiol Cell Physiol. 2000;278:C500–8.
doi: 10.1152/ajpcell.2000.278.3.C500
pubmed: 10712238
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic acids research. 2017;45:W98–102.
doi: 10.1093/nar/gkx247
pubmed: 28407145
pmcid: 5570223
Nepstad I, Hatfield KJ, Grønningsæter IS, Reikvam H. The PI3K-Akt-mTOR signaling pathway in human acute myeloid leukemia (AML) cells. Int J Mol Sci. 2020;21:2907.
Ebi H, Costa C, Faber AC, Nishtala M, Kotani H, Juric D, et al. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. Proc Natl Acad Sci USA 2013;110:21124–9.
doi: 10.1073/pnas.1314124110
pubmed: 24327733
pmcid: 3876254
Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36:320–8.
doi: 10.1016/j.tibs.2011.03.006
pubmed: 21531565
pmcid: 3112285
Won JK, Yang HW, Shin SY, Lee JH, Heo WD, Cho KH. The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor. J Mol Cell Biol. 2012;4:153–63.
doi: 10.1093/jmcb/mjs021
pubmed: 22561840
Caplan M, Wittorf KJ, Weber KK, Swenson SA, Gilbreath TJ, Willow Hynes-Smith R, et al. Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML. Leukemia. 2022;36:1296–305.
Hynes-Smith RW, Swenson SA, Vahle H, Wittorf KJ, Caplan M, Amador C, et al. Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia. Cancers. 2019;11:1717.
Swenson SA, Gilbreath TJ, Vahle H, Hynes-Smith RW, Graham JH, Law HC, et al. UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells. Blood. 2020;136:299–312.
doi: 10.1182/blood.2019002102
pubmed: 32325489
pmcid: 7365918
Buckley SM, Aranda-Orgilles B, Strikoudis A, Apostolou E, Loizou E, Moran-Crusio K, et al. Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. Cell Stem Cell. 2012;11:783–98.
doi: 10.1016/j.stem.2012.09.011
pubmed: 23103054
pmcid: 3549668
Deutsch EW, Csordas A, Sun Z, Jarnuczak A, Perez-Riverol Y, Ternent T, et al. The ProteomeXchange consortium in 2017: supporting the cultural change in proteomics public data deposition. Nucleic Acids Res. 2017;45(D1):D1100-D1106.