Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling.
Receptors, CXCR4
/ metabolism
Humans
Animals
Signal Transduction
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Dexamethasone
/ pharmacology
Type C Phospholipases
/ metabolism
Cell Line, Tumor
Glucocorticoids
/ pharmacology
Mice
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
/ drug therapy
Mice, Inbred NOD
Cell Survival
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 May 2024
29 May 2024
Historique:
received:
15
02
2023
accepted:
15
05
2024
medline:
30
5
2024
pubmed:
30
5
2024
entrez:
29
5
2024
Statut:
epublish
Résumé
Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca
Identifiants
pubmed: 38811530
doi: 10.1038/s41467-024-48818-9
pii: 10.1038/s41467-024-48818-9
doi:
Substances chimiques
Receptors, CXCR4
0
Dexamethasone
7S5I7G3JQL
Type C Phospholipases
EC 3.1.4.-
Glucocorticoids
0
CXCR4 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4557Informations de copyright
© 2024. The Author(s).
Références
Conter, V. et al. EDUCATIONAL REPORT Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia. Leukemia 24, 255–264 (2010).
pubmed: 20016536
doi: 10.1038/leu.2009.250
Hefazi, M. & Litzow, M. R. Recent advances in the biology and treatment of B-cell acute lymphoblastic leukemia. Blood Lymphat. Cancer Targets Ther. 8, 47–61 (2018).
doi: 10.2147/BLCTT.S170351
Serafin, V. et al. Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia. Blood 130, 2750–2761 (2017).
pubmed: 29101238
doi: 10.1182/blood-2017-05-784603
Irving, J. A. E. Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia. Br. J. Haematol. 172, 655–666 (2016).
pubmed: 26568036
doi: 10.1111/bjh.13852
Lauten, M. et al. Prediction of outcome by early bone marrow response in childhood acute lymphoblastic leukemia treated in the ALL-BFM 95 trial: differential effects in precursor B-cell and T-cell leukemia. Haematologica 97, 1048–1056 (2012).
pubmed: 22271901
pmcid: 3396677
doi: 10.3324/haematol.2011.047613
Conter, V. et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115, 3206–3214 (2010).
pubmed: 20154213
doi: 10.1182/blood-2009-10-248146
Meyer, L. K. et al. Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes. J. Clin. Invest. 130, 863–876 (2020).
pubmed: 31687977
pmcid: 6994137
doi: 10.1172/JCI130189
Abdoul-Azize, S., Dubus, I. & Vannier, J. P. Improvement of dexamethasone sensitivity by chelation of intracellular Ca2+ in pediatric acute lymphoblastic leukemia cells through the prosurvival kinase ERK1/2 deactivation. Oncotarget 8, 27339–27352 (2017).
pubmed: 28423696
pmcid: 5432339
doi: 10.18632/oncotarget.16039
Kikuchi, K., Lai, A. Y., Hsu, C. L. & Kondo, M. IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF. J. Exp. Med. 201, 1197–1203 (2005).
pubmed: 15837809
pmcid: 2213146
doi: 10.1084/jem.20050158
Yu, M. et al. PLCγ-dependent mTOR signalling controls IL-7-mediated early B cell development. Nat. Commun. 8, 1457 (2017).
pubmed: 29133930
pmcid: 5684131
doi: 10.1038/s41467-017-01388-5
Kruth, K. A. et al. Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia. Blood 129, 3000–3008 (2017).
pubmed: 28424165
pmcid: 5454339
doi: 10.1182/blood-2017-02-766204
Monteith, G. R., McAndrew, D., Faddy, H. M. & Roberts-Thomson, S. J. Calcium and cancer: targeting Ca2+ transport. Nat. Rev. Cancer 7, 519–530 (2007).
pubmed: 17585332
doi: 10.1038/nrc2171
Roderick, H. L. & Cook, S. J. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat. Rev. Cancer 8, 361–375 (2008).
pubmed: 18432251
doi: 10.1038/nrc2374
Prevarskaya, N., Skryma, R. & Shuba, Y. Calcium in tumour metastasis: new roles for known actors. Nat. Rev. Cancer 11, 609–618 (2011).
pubmed: 21779011
doi: 10.1038/nrc3105
Berditchevski, F., Fennell, E. & Murray, P. G. Calcium-dependent signalling in B-cell lymphomas. Oncogene 40, 6321–6328 (2021).
pubmed: 34625709
pmcid: 8585665
doi: 10.1038/s41388-021-02025-8
de Gorter, D. J. J. et al. Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity 26, 93–104 (2007).
pubmed: 17239630
doi: 10.1016/j.immuni.2006.11.012
Polouliakh, N., Nock, R., Nielsen, F. & Kitano, H. G-protein coupled receptor signaling architecture of mammalian immune cells. PLoS ONE 4, e4189 (2009).
pubmed: 19142232
pmcid: 2615211
doi: 10.1371/journal.pone.0004189
Walliser, C. et al. The phospholipase Cγ2 mutants R665W and L845F identified in ibrutinib-resistant chronic lymphocytic leukemia patients are hypersensitive to the Rho GTPase Rac2 protein. J. Biol. Chem. 291, 22136 (2016).
pubmed: 27542411
pmcid: 5063995
doi: 10.1074/jbc.M116.746842
Wang, D. et al. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 13, 25–35 (2000).
pubmed: 10933392
doi: 10.1016/S1074-7613(00)00005-4
Jackson, J. T., Mulazzani, E., Nutt, S. L. & Masters, S. L. The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration. J. Biol. Chem. 297, 100905 (2021).
pubmed: 34157287
pmcid: 8318911
doi: 10.1016/j.jbc.2021.100905
Schnoeder, T. M. et al. PLCG1 is required for AML1-ETO leukemia stem cell self-renewal. Blood 139, 1080–1097 (2022).
pubmed: 34695195
pmcid: 8854675
doi: 10.1182/blood.2021012778
Liu, T.-M. et al. Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood 126, 61–68 (2015).
pubmed: 25972157
pmcid: 4492196
doi: 10.1182/blood-2015-02-626846
Wist, M. et al. Noncatalytic Bruton’s tyrosine kinase activates PLCγ2 variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells. J. Biol. Chem. 295, 5717–5736 (2020).
pubmed: 32184360
pmcid: 7186163
doi: 10.1074/jbc.RA119.011946
Rocchetti, F. et al. The calcineurin protein phosphatase is dispensable for BCR-ABL-induced B-ALL maintenance, propagation and response to dasatinib. Leukemia 31, 248–251 (2017).
pubmed: 27694923
doi: 10.1038/leu.2016.269
Müller, M. R. & Rao, A. NFAT, immunity and cancer: a transcription factor comes of age. Nat. Rev. Immunol. 10, 645–656 (2010).
pubmed: 20725108
doi: 10.1038/nri2818
Bucher, P. et al. Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma. Blood 135, 121–132 (2020).
pubmed: 31794606
doi: 10.1182/blood.2019001866
Eswaran, J. et al. The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia. Leukemia 29, 1623–1631 (2015).
pubmed: 25943180
doi: 10.1038/leu.2015.113
Rickert, R. C. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat. Rev. Immunol. 13, 578–591 (2013).
pubmed: 23883968
doi: 10.1038/nri3487
Mangum, D. S. et al. VPREB1 deletions occur independent of lambda light chain rearrangement in childhood acute lymphoblastic leukemia. Leukemia 28, 216–220 (2013).
pubmed: 23881307
pmcid: 4043450
doi: 10.1038/leu.2013.223
Geng, H. et al. Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia. Cancer Cell 27, 409–425 (2015).
pubmed: 25759025
pmcid: 4618684
doi: 10.1016/j.ccell.2015.02.003
Klein, F. et al. The BCR-ABL1 kinase bypasses selection for the expression of a pre-B cell receptor in pre-B acute lymphoblastic leukemia cells. J. Exp. Med. 199, 673–685 (2004).
pubmed: 14993251
pmcid: 2213306
doi: 10.1084/jem.20031637
Trageser, D. et al. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. J. Exp. Med. 206, 1739–1753 (2009).
pubmed: 19620627
pmcid: 2722172
doi: 10.1084/jem.20090004
Nagasawa, T. et al. Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Proc. Natl Acad. Sci. USA 93, 14726–14729 (1996).
pubmed: 8962122
pmcid: 26203
doi: 10.1073/pnas.93.25.14726
Nishii, K. et al. Survival of human leukaemic B-cell precursors is supported by stromal cells and cytokines: association with the expression of bcl-2 protein. Br. J. Haematol. 105, 701–710 (1999).
pubmed: 10354135
doi: 10.1046/j.1365-2141.1999.01380.x
Kohlmann, A. et al. An international standardization programme towards the application of gene expression profiling in routine leukaemia diagnostics: the Microarray Innovations in LEukemia study prephase. Br. J. Haematol. 142, 802–807 (2008).
pubmed: 18573112
pmcid: 2654477
doi: 10.1111/j.1365-2141.2008.07261.x
Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
pubmed: 22460905
pmcid: 3320027
doi: 10.1038/nature11003
Haferlach, T. 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. 28, 2529–2537 (2010).
pubmed: 20406941
pmcid: 5569671
doi: 10.1200/JCO.2009.23.4732
Rhodes, D. R. et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6, 1–6 (2004).
pubmed: 15068665
pmcid: 1635162
doi: 10.1016/S1476-5586(04)80047-2
Tang, Z. et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45, W98–W102 (2017).
pubmed: 28407145
pmcid: 5570223
doi: 10.1093/nar/gkx247
Berridge, M. J. Inositol trisphosphate and calcium signalling. Nature 361, 315–325 (1993).
pubmed: 8381210
doi: 10.1038/361315a0
Guo, B., Su, T. T. & Rawlings, D. J. Protein kinase C family functions in B-cell activation. Curr. Opin. Immunol. 16, 367–373 (2004).
pubmed: 15134787
doi: 10.1016/j.coi.2004.03.012
Diver, J. M., Sage, S. O. & Rosado, J. A. The inositol trisphosphate receptor antagonist 2-aminoethoxydiphenylborate (2-APB) blocks Ca2+ entry channels in human platelets: cautions for its use in studying Ca2+ influx. Cell Calcium 30, 323–329 (2001).
pubmed: 11733938
doi: 10.1054/ceca.2001.0239
Chougule, R. A., Shah, K., Moharram, S. A., Vallon-Christersson, J. & Kazi, J. U. Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation. NPJ Genom. Med. 4, 7 (2019).
pubmed: 30962949
pmcid: 6449402
doi: 10.1038/s41525-019-0082-y
Holleman, A. et al. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N. Engl. J. Med. 351, 533–542 (2004).
pubmed: 15295046
doi: 10.1056/NEJMoa033513
Wei, G. et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 10, 331–342 (2006).
pubmed: 17010674
doi: 10.1016/j.ccr.2006.09.006
Staal, F. J. T. et al. Genome-wide expression analysis of paired diagnosis–relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype. Leukemia 24, 491–499 (2010).
pubmed: 20072147
doi: 10.1038/leu.2009.286
Hogan, L. E. et al. Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. Blood 118, 5218–5226 (2011).
pubmed: 21921043
pmcid: 3217405
doi: 10.1182/blood-2011-04-345595
Bachmann, P. S. et al. Divergent mechanisms of glucocorticoid resistance in experimental models of pediatric acute lymphoblastic leukemia. Cancer Res. 67, 4482–4490 (2007).
pubmed: 17483364
doi: 10.1158/0008-5472.CAN-06-4244
Owusu Obeng, E. et al. Phosphoinositide-dependent signaling in cancer: a focus on phospholipase C isozymes. Int. J. Mol. Sci. 21, 2581 (2020).
pubmed: 32276377
pmcid: 7177890
doi: 10.3390/ijms21072581
Hetzel, S. et al. Acute lymphoblastic leukemia displays a distinct highly methylated genome. Nat. Cancer 3, 768–782 (2022).
pubmed: 35590059
pmcid: 9236905
doi: 10.1038/s43018-022-00370-5
Zhou, W. et al. DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat. Genet. 50, 591–602 (2018).
pubmed: 29610480
pmcid: 5893360
doi: 10.1038/s41588-018-0073-4
Andersson, A. et al. Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status. Leukemia 21, 1198–1203 (2007).
pubmed: 17410184
doi: 10.1038/sj.leu.2404688
Dar, A. et al. Chemokine receptor CXCR4–dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells. Nat. Immunol. 6, 1038–1046 (2005).
pubmed: 16170318
doi: 10.1038/ni1251
Guinamard, R. et al. B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4. J. Exp. Med. 189, 1461–1466 (1999).
pubmed: 10224286
pmcid: 2193069
doi: 10.1084/jem.189.9.1461
Förster, R. et al. Intracellular and surface expression of the HIV-1 coreceptor CXCR4/fusin on various leukocyte subsets: rapid internalization and recycling upon activation. J. Immunol. 160, 1522–1531 (1998).
pubmed: 9570576
doi: 10.4049/jimmunol.160.3.1522
Tarasova, N. I., Stauber, R. H. & Michejda, C. J. Spontaneous and ligand-induced trafficking of CXC-chemokine receptor 4. J. Biol. Chem. 273, 15883–15886 (1998).
pubmed: 9632631
doi: 10.1074/jbc.273.26.15883
Wysoczynski, M. et al. Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient. Blood 105, 40–48 (2005).
pubmed: 15328152
doi: 10.1182/blood-2004-04-1430
Cheung, H. W. et al. Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. Proc. Natl Acad. Sci. USA 108, 12372–12377 (2011).
pubmed: 21746896
pmcid: 3145679
doi: 10.1073/pnas.1109363108
Randhawa, S. et al. Effects of pharmacological and genetic disruption of CXCR4 chemokine receptor function in B-cell acute lymphoblastic leukaemia. Br. J. Haematol. 174, 425–436 (2016).
pubmed: 27071778
pmcid: 4959949
doi: 10.1111/bjh.14075
Juarez, J., Bradstock, K. F., Gottlieb, D. J. & Bendall, L. J. Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia 17, 1294–1300 (2003).
pubmed: 12835717
doi: 10.1038/sj.leu.2402998
Ghosh, M. C. et al. Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck. Blood 113, 575–584 (2009).
pubmed: 18840710
pmcid: 2628365
doi: 10.1182/blood-2008-04-151803
Curnow, S. J. et al. Topical glucocorticoid therapy directly induces up-regulation of functional CXCR4 on primed T lymphocytes in the aqueous humor of patients with uveitis. J. Immunol. 172, 7154–7161 (2004).
pubmed: 15153539
doi: 10.4049/jimmunol.172.11.7154
Shimba, A. et al. Glucocorticoids drive diurnal oscillations in T cell distribution and responses by inducing interleukin-7 receptor and CXCR4. Immunity 48, 286–298.e6 (2018).
pubmed: 29396162
doi: 10.1016/j.immuni.2018.01.004
Nagase, H. et al. Glucocorticoids preferentially upregulate functional CXCR4 expression in eosinophils. J. Allergy Clin. Immunol. 106, 1132–1139 (2000).
pubmed: 11112897
doi: 10.1067/mai.2000.110923
Schweingruber, N. et al. Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses. Acta Neuropathol. 127, 713–729 (2014).
pubmed: 24488308
pmcid: 4943522
doi: 10.1007/s00401-014-1248-4
Wendt, E. et al. Glucocorticoids suppress CCR9-mediated chemotaxis, calcium flux, and adhesion to MAdCAM-1 in human T cells. J. Immunol. 196, 3910–3919 (2016).
pubmed: 27016601
doi: 10.4049/jimmunol.1500619
Mishra, R. K., Shum, A. K., Platanias, L. C., Miller, R. J. & Schiltz, G. E. Discovery and characterization of novel small-molecule CXCR4 receptor agonists and antagonists. Sci. Rep. 6, 30155 (2016).
pubmed: 27456816
pmcid: 4960487
doi: 10.1038/srep30155
Ping, Y.-Q. et al. Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex. Nature 589, 620–626 (2021).
pubmed: 33408414
doi: 10.1038/s41586-020-03083-w
Cifone, M. G. et al. Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood 93, 2282–2296 (1999).
pubmed: 10090938
doi: 10.1182/blood.V93.7.2282
Abdoul-Azize, S., Buquet, C., Li, H., Picquenot, J.-M. & Vannier, J.-P. Integration of Ca2+ signaling regulates the breast tumor cell response to simvastatin and doxorubicin. Oncogene 37, 4979–4993 (2018).
pubmed: 29795329
doi: 10.1038/s41388-018-0329-6
Selvanathan, S. P. et al. Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing. Proc. Natl Acad. Sci. USA 112, E1307–E1316 (2015).
pubmed: 25737553
pmcid: 4371969
doi: 10.1073/pnas.1500536112
Kocak, H. et al. Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma. Cell Death Dis. 4, e586 (2013).
pubmed: 23579273
pmcid: 3668636
doi: 10.1038/cddis.2013.84
Cardesa-Salzmann, T. M. et al. High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy. Haematologica 96, 996–1001 (2011).
pubmed: 21546504
pmcid: 3128218
doi: 10.3324/haematol.2010.037408
Li, Z. et al. Identification of a 24-gene prognostic signature that improves the European LeukemiaNet risk classification of acute myeloid leukemia: an international collaborative study. J. Clin. Oncol. 31, 1172–1181 (2013).
pubmed: 23382473
pmcid: 3595425
doi: 10.1200/JCO.2012.44.3184