Activities of SYK and PLCγ2 Predict Apoptotic Response of CLL Cells to SRC Tyrosine Kinase Inhibitor Dasatinib
Abstract
Purpose B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL. Experimental design Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors. Results Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cgamma2, correlate well with the apoptotic response of CLL cells to dasatinib. Conclusions Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cgamma2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathog…
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SYK/PLCγ2 signaling activity correlated with cell death induced by treatment with the Src tyrosine kinase inhibitor Dasatinib in CLL and DLBCL.
“SYK/PLCγ2 activity is also suggested as a potential biomarker for responsiveness in the treatment of CLL and DLBCL, as their signaling activity correlated with cell death induced by treatment with the Src tyrosine kinase inhibitor, Dasatinib (133, 134).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [134]
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Montero, J. C., Seoane, S., Ocaña, A., & Pandiella, A. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2616 · Cited by 298 · see citing works
Cheng, S.-H., Ma, J., Guo, A., Lu, P., Leonard, J., Coleman, M., Liu, M., Buggy, J., Furman, R., & Wang, Y.-L. (2014) · Leukemia · doi:10.1038/leu.2013.358 · Cited by 179 · see citing works
Self-citationCheng, S.-H., Guo, A., Lu, P., Ma, J., Coleman, M., & Wang, Y.-L. (2014) · Leukemia · doi:10.1038/leu.2014.263 · Cited by 155 · see citing works
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Poh, A., O'Donoghue, R., & Ernst, M. (2015) · OncoTarget · doi:10.18632/oncotarget.4199 · Cited by 121 · see citing works
“Dasatinib SFKs, BCR/ ABL, c-Kit, Ephrins, RTKs Reduced [174–177] Increased [178–180] Reduced [181, 182] Restored [123, 134] Prostate [183] and breast [184, 185] cancer”
BackgroundThe role of PLCγ2 in immunological disorders, cancer, and neurodegeneration
Jackson, J. T., Mulazzani, E., Nutt, S. L., & Masters, S. L. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100905 · Cited by 113 · see citing works
“SYK/PLCγ2 activity is also suggested as a potential biomarker for responsiveness in the treatment of CLL and DLBCL, as their signaling activity correlated with cell death induced by treatment with the Src tyrosine kinase inhibitor, Dasatinib (133, 134).”
BackgroundSYK inhibition and response prediction in diffuse large B-cell lymphoma.
Cheng, S.-H., Coffey, G., Zhang, X., Shaknovich, R., Song, Z., Lu, P., Pandey, A., Melnick, A. M., Sinha, U., & Wang, Y. (2011) · Blood · doi:10.1182/blood-2011-02-333773 · Cited by 111 · see citing works
Self-citationCharacterization of ibrutinib-sensitive and -resistant mantle lymphoma cells
Ma, J., Lu, P., Guo, A., Cheng, S., Zong, H., Martin, P., Coleman, M., & Wang, Y. L. (2014) · British Journal of Haematology · doi:10.1111/bjh.12974 · Cited by 90 · see citing works
“…events better correlate with cellular responses of cells to the drug, we measured the phosphorylation levels of ERK and AKT in ibrutinib-treated MCL cells using phospho-flow assays that are sensitive and quantitative (Yang et al, 2008; Lu et al, 2009; Song et al, 2010; Cheng et al, 2011).”
BackgroundMethodInfluentialSelf-citationIdentification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL
Sharma, S., Galanina, N., Guo, A., Lee, J., Kadri, S., Van Slambrouck, C., Long, B., Wang, W., Ming, M., Furtado, L. V., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11932 · Cited by 90 · see citing works
Self-citationMcCaig, A. M., Cosimo, E., Leach, M. T. J., & Michie, A. (2011) · British Journal of Haematology · doi:10.1111/j.1365-2141.2010.08507.x · Cited by 80 · see citing works
“Song et al (2010) concluded that Syk inhibitors may have more therapeutic potential than dasatinib in CLL.”
BackgroundResultMicroenvironment dependency in Chronic Lymphocytic Leukemia: The basis for new targeted therapies.
ten Hacken, E., & Burger, J. (2014) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2014.07.003 · Cited by 64 · see citing works
“In vitro, dasatinib has been demonstrated to inhibit BCR signaling and survival of CLL cells (Veldurthy et al., 2008; Song et al., 2010), also in the presence of microenvironmental stimuli including CD40L and IL4 (McCaig et al.”
BackgroundThe degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia
Roy, C. L., Deglesne, P., Chevallier, N., Beitar, T., Éclache, V., Quettier, M., Boubaya, M., Letestu, R., Lévy, V., Cymbalista, F., et al. (2012) · Blood · doi:10.1182/blood-2011-12-397158 · Cited by 62 · see citing works
Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia.
ten Hacken, E., Scielzo, C., Bertilaccio, M. T., Scarfò, L., Apollonio, B., Barbaglio, F., Stamatopoulos, K., Ponzoni, M., Ghia, P., & Caligaris-cappio, F. (2012) · Blood · doi:10.1182/blood-2012-09-457119 · Cited by 56
Marignac, V. L. M., Smith, S. E., Toban, N., Bazile, M., & Aloyz, R. S. (2013) · Oncotarget · doi:10.18632/oncotarget.1508 · Cited by 54 · see citing works
Zauli, G., Voltan, R., Bosco, R., Melloni, E., Marmiroli, S., Rigolin, G. M., Cuneo, A., & Secchiero, P. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2572 · Cited by 49 · see citing works
“emanates via Syk and PLC-γ to the phosphatidylinositol (PI) 3-kinase/Akt axis (5, 26)”
p53 and autophagy contribute to dasatinib resistance in primary CLL lymphocytes.
Amrein, L., Soulières, D., Johnston, J., & Aloyz, R. (2011) · Leukemia research : a Forum for Studies on Leukemia and Normal Hemopoiesis · doi:10.1016/j.leukres.2010.05.029 · Cited by 54
The Syk kinase as a therapeutic target in leukemia and lymphoma
Efremov, D. G., & Laurenti, L. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.570329 · Cited by 55 · see citing works
“Dasatinib Inhibitor of Src family kinases; does not inhibit Syk directly but blocks Syk activation by inhibiting the upstream Src kinases Induces apoptosis in primary CLL cells; apoptotic response depends on degree of Syk inhibition [65]”
BackgroundGuo, A., Lu, P., Galanina, N., Nabhan, C., Smith, S. M., Coleman, M., & Wang, Y. L. (2015) · OncoTarget · doi:10.18632/oncotarget.6727 · Cited by 51 · see citing works
“Veldurthy et al. [40] and our group [41] have both reported that dasatinib (primarily targeting LYN) generated a better in vitro apoptotic response in UM-CLL than M-CLL.”
Self-citationLu, P., Wang, S.-C., Franzen, C. A., Venkataraman, G., Mcclure, R., Li, L., Wu, W., Niu, N.-F., Sukhanova, M., Pei, J., et al. (2021) · Blood Cancer Journal · doi:10.1038/s41408-021-00429-z · Cited by 48 · see citing works
Self-citationHayden, R., Pratt, G., Roberts, C., Drayson, M., & Bunce, C. (2012) · Leukemia and Lymphoma · doi:10.3109/10428194.2011.610014 · Cited by 44 · see citing works
McCaig, A. M., Cosimo, E., Leach, M. T. J., & Michie, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048929 · Cited by 38 · see citing works
“Both our group and others have demonstrated that dasatinib inhibits BCR signal transduction and blocks BCR-mediated survival of CLL cells [9,10,11].”
BackgroundStepanek, O., Draber, P., Drobek, A., Horejsi, V., & Brdicka, T. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202401 · Cited by 31 · see citing works
E2A-PBX1 remodels oncogenic signaling networks in B-cell precursor acute lymphoid leukemia
Duque-Afonso, J., Lin, C.-H., Han, K., Wei, M., Feng, J., Kurzer, J. H., Schneidawind, C., Wong, S., Bassik, M., & Cleary, M. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1899 · Cited by 28 · see citing works
Spleen tyrosine kinase as a molecular target for treatment of leukemias and lymphomas
Uçkun, F., & Qazi, S. (2010) · Expert Review of Anticancer Therapy · doi:10.1586/era.10.112 · Cited by 27 · see citing works
Kater, A., Spiering, M., Liu, R. D. K., Raa, G. D. T., Slinger, E., Tonino, S., Beckers, M., Daenen, S., Doorduijn, J., Lankheet, N., et al. (2014) · Leukemia research : a Forum for Studies on Leukemia and Normal Hemopoiesis · doi:10.1016/j.leukres.2013.10.004 · Cited by 25 · see citing works
NOVEL AGENTS AND EMERGING STRATEGIES FOR TARGETING THE B-CELL RECEPTOR PATHWAY IN CLL
Efremov, D. G., Wiestner, A. U., & Laurenti, L. (2012) · Mediterranean Journal of Hematology and Infectious Diseases · doi:10.4084/mjhid.2012.067 · Cited by 20 · see citing works
“Targeting of LYN with SRC-family kinase inhibitors, such as PP2 and Dasatinib, induces leukemic cell apoptosis.(18,62,63) However, it is still uncertain whether the cytotoxic effect of these”
BackgroundAmrein, P. (2011) · Leukemia and Lymphoma · doi:10.3109/10428194.2011.555890 · Cited by 24 · see citing works
“Studies have shown that dasatinib induces apoptosis in freshly isolated CLL cells, particularly in those with unmutated IgVH genes, and inhibits SFK phosphorylation [41,42].”
BackgroundDebant, M., Hémon, P., Brigaudeau, C., Renaudineau, Y., & Mignen, O. (2015) · The International Journal of Developmental Biology · doi:10.1387/ijdb.150204om · Cited by 25 · see citing works
Guo, A., Lu, P., Lee, J. C., Zhen, C., Chiosis, G., & Wang, Y.-L. (2017) · Oncogene · doi:10.1038/onc.2016.494 · Cited by 21 · see citing works
Self-citationKeizer, E. M., Wösten, H., & de Cock, H. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.534118 · Cited by 20 · see citing works
“Since dasatinib not only inhibits the activation of the EphA2 receptor but acts as a broad range tyrosine kinase inhibitor, also inhibiting BRC-Abl and Scr and Syk family kinases (Schade et al., 2008; Baell and Holloway, 2010; Song et al., 2010), we also used an EphA2-specific antibody.”
MethodInhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2.
Wu, W., Wang, W., Franzen, C. A., Guo, H., Lee, J., Li, Y., Sukhanova, M., Sheng, D., Venkataraman, G., Mei, M., et al. (2018) · Blood Advances · doi:10.1182/blood-2018-99-118598 · Cited by 18
Self-citationSlupsky, J. R. (2014) · Scientifica · doi:10.1155/2014/208928 · Cited by 12 · see citing works
Mato, A. R., Jauhari, S., & Schuster, S. J. (2015) · American Journal of Hematology · doi:10.1002/ajh.24021 · Cited by 15 · see citing works
“As potential biomarkers of response, enhanced pretreatment SYK and phospholipase C gamma2 (PLCg2) activity levels predicted an apoptotic response to dasatinib in CLL cells [61].”
BackgroundSerpa, M., Bendit, I., Seguro, F., Xavier, F., Cavalcante, M., Steinbaum, D., Nardinelli, L., Aldred, V., de Paula, H. M., & Dorlhiac-Llacer, P. (2010) · Acta Haematologica · doi:10.1159/000318009 · Cited by 14
“Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western World. It is characterized by the proliferation of mature CD5+ B cells, and its incidence is increased in men >65 years of age [ ,”
BackgroundPalomba, M., Piersanti, K., Ziegler, C. G. K., Decker, H., Cotari, J., Bantilan, K., Rijo, I., Gardner, J., Heaney, M., Bemis, D., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0079987 · Cited by 13 · see citing works
“reported how total SYK and PLCc2 phosphorylation upon dasatinib treatment (a SRC inhibitor) predicted the apoptotic response to the drug [45].”
BackgroundKuckertz, M., Patz, M., Veldurthy, A., Gehrke, I., Claasen, J., Frenzel, L., Wendtner, C., Hallek, M., & Krause, G. (2012) · Oncology Research and Treatment · doi:10.1159/000341081 · Cited by 13
Hutchinson, C., Natarajan, S. K., Johnson, S. M., Adams, J., Rees-Unwin, K., & Burthem, J. (2014) · Experimental Hematology & Oncology · doi:10.1186/2162-3619-3-7 · Cited by 8
Protein Kinases: Emerging Therapeutic Targets in Chronic Lymphocytic Leukemia
Balakrishnan, K., & Gandhi, V. (2012) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2012.668526 · Cited by 8 · see citing works
“As opposed to Src kinases, inhibition of SYK and PLCg2 quantitatively correlated with the degree of dasatinib-induced apoptotic response in CLL [37] implicating SYK as an important therapeutic target in B-CLL.”
BackgroundBourgne, C., Janel, A., Berger, J., Rapatel, C., Tournilhac, O., Hermet, É., Guerci, A., Lioret, F., Briançon, A., Bamdad, M., et al. (2015) · Leukemia research : a Forum for Studies on Leukemia and Normal Hemopoiesis · doi:10.1016/j.leukres.2014.11.014 · Cited by 6
In vivo, ex vivo and in vitro dasatinib activity in chronic lymphocytic leukemia
Giannopoulos, K., Karczmarczyk, A., Karp, M., Bojarska-Junak, A., Kosior, K., Kowal, M., Tomczak, W., Hus, M., Machnicki, M. M., & Stokłosa, T. (2021) · Oncology Letters · doi:10.3892/ol.2021.12546 · Cited by 5 · see citing works
“The preclinical effi‐ cacy of dasatinib is due to inhibition of LYN and SFK kinases in CLL cells, overcoming pro‐survival signals from BCR and leading to apoptosis (8,20,31,32).”
BackgroundChen, X.-G., Zhu, X.-M., Wei, Z., & Lv, Q.-X. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29294 · Cited by 3 · see citing works
“Also, Song et al10 observed a strong correlation between PLCγ2 activity suppression and the maximal rate of chronic lymphocytic leukemia cell death, thus validating the tumor‐promoting function of PLCγ2 in this type of leukemia.”
BackgroundProteomics-based identification of cancer-associated proteins in chronic lymphocytic leukaemia
Alsagaby, S., Brewis, I., Vijayakumar, R., Alhumaydhi, F., Alwashmi, A. S., Alharbi, N., Abdulmonem, W. A., Premanathan, M., Pratt, G., Fegan, C., et al. (2021) · Electronic Journal of Biotechnology · doi:10.1016/j.ejbt.2021.04.006 · Cited by 2 · see citing works
Lu, P., Franzen, C. A., Vistarop, A., Efimov, A., Shahriyar, S. A., Wang, S.-C., Rao, S., Messmer, M. R., Nakhoda, S., Cukierman, E., et al. (2025) · Blood neoplasia · doi:10.1016/j.bneo.2025.100142 · Cited by 1 · see citing works
“19,20 Recognizing this deficiency, we have developed a novel and simple ex vivo model that incorporates the tumor microenvironment (TME).”
Self-citationBioinformatic mining of kinase inhibitors that regulate autophagy through kinase signaling pathways.
Yang, Y., Ma, B., Jin, Y., Ben, W., Zhang, D., Jiang, K., Feng, S.-J., Huang, L., & Zheng, J.-H. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.2663 · Cited by 1 · see citing works
Quettier, M. (2015) · doi:10.70675/3dc44105z2574z4790zb6abz85a45bdf97bf
“En effet, le pourcentage de diminution de la phosphorylation de PLCγ2 dans les cellules traitées avec le Dasatinib est corrélé à la mortalité cellulaire [259].”
BackgroundSignal Transduction Therapies for Treatment of Chronic Leukemias
Kaymaz, B. (2014) · Global Journal of Hematology and Blood Transfusion · doi:10.15379/2408-9877.2014.01.01.5
“Targeting LYN with SRC-family kinase inhibitors such as PP2 and Dasatinib resulted in induced leukemic cell apoptosis [29-30].”
BackgroundPalomba, M., Piersanti, K., Ziegler, C. G. K., Cotari, J., Balderas, R., Malek, S. N., Seymour, E. K., Zelenetz, A., van den Brink, M. R., & Altan-Bonnet, G. (2013) · Cancer Research · doi:10.1158/1538-7445.am2013-2886
“reported how total SYK and PLCc2 phosphorylation upon dasatinib treatment (a SRC inhibitor) predicted the apoptotic response to the drug [45].”
BackgroundMethods for SNP Regression Analysis in Clinical Studies
LeBlanc, M., Goldman, B., & Kooperberg, C. (2012) · doi:10.1201/b11800-37
“Investigations of the association of patient outcome with a few candidate single nucleotide polymorphisms (SNPs) or much larger numbers of SNPs have been undertaken in various therapeutic studies in oncology (e.g., Durie et al. 2009, Song et al. 2010).”
BackgroundIn Vitro Sensitivity Testing in the Assessment of Anti-CLL Drug Candidates
Krause, G., Kuckertz, M., Kerwien, S., Patz, M., & Hallek, M. (2012) · InTech eBooks · doi:10.5772/27087
“The extent of dasatinib-induced apoptosis in CLL cells corresponds to the concomitant decrease in the phosphorylation of the direct SFK substrates Syk and phospholipase C-γ (Song et al., 2010).”
Background
- Authors
- Song, Z., Lu, P., Furman, R. R., Leonard, J. P., Martin, P., Tyrell, L., Lee, F. Y., Knowles, D. M., Coleman, M., & Wang, Y. L.
- Affiliations
- Bristol-Myers Squibb (United States) (US)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2010-01-14
- Volume
- 16
- Issue
- 2
- Pages
- 587-599
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2042132765
- Cited by
- 59
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2021: 7 · 2020: 1 · 2019: 1 · 2017: 1 · 2016: 2 · 2015: 5 · 2014: 13 · 2013: 6 · 2012: 9
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Weill Cornell Medical College
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- chronic lymphocytic leukemia, dasatinib, Syk, PLCγ2, Src family kinases, B cell receptor signaling, apoptosis, reactive oxygen species, predictive biomarkers, therapeutic target
- MeSH terms
- Dasatinib, Syk Kinase, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Enzyme Activation, Female, Humans, Male, Middle Aged, Prognosis, Protein-Tyrosine Kinases, Pyrimidines, Thiazoles, Tumor Cells, Cultured, Leukemia, Lymphocytic, Chronic, B-Cell, Cell Death, Apoptosis, src-Family Kinases, Protein Kinase Inhibitors, Intracellular Signaling Peptides and Proteins, Phospholipase C gamma, Biomarkers, Pharmacological
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