Sensitivity of chronic lymphocytic leukemia cells to chemotherapeutic drugs ex vivo depends on expression status of cell surface receptors
DOI:
https://doi.org/10.32471/exp-oncology.2312-8852.vol-42-no-1.14093Keywords:
cell surface receptors, chemosensitivity., chemotherapeutic drugs, chronic lymphocytic leukemia B cells, ex vivoAbstract
Summary. Response of chronic lymphocytic leukemia (CLL) patients to classical chemoimmunotherapy that remains the main strategy in treatment of this disease is strikingly variable. This issue requires the finding of biomarkers which could predict efficiency of drug administration and choose the best treatment option for each patient individually. The aim of this study was to find out association between cell surface receptors expression levels and CLL B cells sensitivity to chemotherapeutic drugs ex vivo. Materials and Methods: The study was performed on malignant B cells isolated from peripheral blood of primary CLL patients. Flow cytometry, qPCR, ex vivo drug sensitivity assay, and cell viability assay were used in this study. Results: The high CD5 expression level was linked to better bendamustine (BEN) and cyclophosphamide (CP) CLL B cells response in contrast to B cells with low CD5 expression. Sensitivity of CLL B cells to CP also could be predicted by high level of CD20 expression. Expression of CD38 and high levels of CD37 and CD40 showed CLL B cells resistance to BEN ex vivo. CLL B cells sensitivity to analyzed chemotherapeutic drugs was not dependent on CD22 expression status. The CD180 expression was detected in CLL B cells which were more susceptible to fludarabine and cyclophosphamide (FC) combinatory action. CLL B cells that coexpressed CD150 and CD180 on the cell surface were characterized by significantly decreased cell viability under fludarabine (FLU) exposure alone or FC in comparison with CD150-CD180- B cells. Cell surface expression level of CD150 was not associated with CLL B cells chemosensitivity. However, high mRNA expression level of mCD150 isoform in CLL B cells was linked to their FLU sensitivity and CP resistance, while high nCD150 mRNA expression level showed resistance to FLU. Simultaneous CD150 and CD180 ligation increased FLU resistance, but BEN susceptibility of CLL B cells. CD150 and CD180 alone or in combination are involved in upregulation of CD20 cell surface expression. Conclusion: Expression status of the CD5, CD20, CD37, CD38, CD40, CD150, and CD180 cell surface receptors could be used in prediction CLL B cells sensitivity to FLU, CP, BEN and FC ex vivo. Moreover, CD150 and CD180 receptors are involved in regulation of CLL B cells susceptibility to FLU and BEN. The CD150 and CD180 are positive regulators of CD20 expression that could make CD150+CD180+ CLL B cells more responsive to CD20-based immunotherapy.
References
Bosch F, Dalla-Favera R. Chronic lymphocytic leukaemia: from genetics to treatment. Nat Rev Clin Oncol 2019; 16: 684–701.
Jain N, O’Brien S. Initial treatment of CLL: integrating biology and functional status. Blood 2015; 126: 463–70.
Shanafelt TD, Rabe KG, Kay NE, et al. Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia. Cancer 2010; 116: 4777–87.
Blumenthal RD, Goldenberg DM. Methods and goals for the use of in vitro and in vivo chemosensitivity testing. Mol Biotechnol 2007; 35: 185–97.
Montraveta A, Lee-Vergés E, Roldán J, et al. CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia. Oncotarget 2015; 7: 5507–20.
Kost SE, Bouchard ED, LaBossiere E, et al. Cross-resistance and synergy with bendamustine in chronic lymphocytic leukemia. Leuk Res 2016; 50: 63–71.
Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014; 123: 3247–54.
Gordiienko I, Shlapatska L, Kholodniuk V, et al. The interplay of CD150 and CD180 receptor pathways contribute to the pathobiology of chronic lymphocytic leukemia B cells by selective inhibition of Akt and MAPK signaling. PLoS One 2017; 12: e0185940.
Gordiienko IM, Shlapatska LM, Kovalevska LM, et al. Differential expression of CD150/SLAMF1 in normal and malignant B cells on the different stages of maturation. Exp Oncol 2016; 38: 101–7.
Gordiienko I, Shlapatska L, Kholodniuk VM, et al. CD150 and CD180 are involved in regulation of transcription factors expression in chronic lymphocytic leukemia cells. Exp Oncol 2017; 39: 291–8.
Engelhard M. Anti-CD20 antibody treatment of non-Hodgkin lymphomas. Clin Immunol 2016; 172: 101–4.
Eichhorst B, Cramer P, Hallek M. Initial therapy of chronic lymphocytic leukemia. Semin Oncol 2016; 43: 241–50.
Prevodnik VK, Lavrencak J, Horvat M, et al. The predictive significance of CD20 expression in B-cell lymphomas. Diagn Pathol 2011; 6: 33.
Huskova H, Korecka K, Karban J, et al. Oncogenic microRNA-155 and its target PU.1: an integrative gene expression study in six of the most prevalent lymphomas. Int J Hematol 2015; 102: 441–50.
Vogenberg FR, Isaacson Barash C, Pursel M. Personalized medicine: part 1: evolution and development into theranostics. P T 2010; 35: 560–76.
Varady G, Cserepes J, Nemeth A, et al. Cell surface membrane proteins as personalized biomarkers: where we stand and where we are headed. Biomark Med 2013; 7: 803–19.
Mehta S, Shelling A, Muthukaruppan A, et al. Predictive and prognostic molecular markers for cancer medicine. Ther Adv Med Oncol 2010; 2: 125–48.
Fabbri G, Dalla-Favera R. The molecular pathogenesis of chronic lymphocytic leukaemia. Nat Rev Cancer 2016; 16: 145–62.
Barrientos JC. Sequencing of chronic lymphocytic leukemia therapies. Hematology Am Soc Hematol Educ Program 2016; 2016: 128–36.
Cramer P, Langerbeins P, Eichhorst B, et al. Advances in first-line treatment of chronic lymphocytic leukemia: current recommendations on management and first-line treatment by the German CLL Study Group (GCLLSG). Eur J Haematol 2016; 96: 9–18.
Blom K, Nygren P, Larsson R, et al. Predictive value of ex vivo chemosensitivity assays for individualized cancer chemotherapy: a meta-analysis. SLAS Technol 2017; 22: 306–14.
Rogalinska M, Blonski JZ, Goralski P, et al. Relationship between in vitro drug sensitivity and clinical response of patients to treatment in chronic lymphocytic leukemia. Int J Oncol 2015; 46: 1259–67.
Podhorecka M, Klimek P, Chocholska S, et al. The rate of in vitro fludarabine-induced peripheral blood and bone marrow cell apoptosis may predict the chemotherapy outcome in patients with chronic lymphocytic leukemia. Eur J Clin Pharmacol 2015; 71: 1121–7.
Ten Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: Implications for disease pathogenesis and treatment. Biochim Biophys Acta 2016; 1863: 401–13.
Ferrer G, Montserrat E. Critical molecular pathways in CLL therapy. Mol Med 2018; 24: 9.
Vaisitti T, Audrito V, Serra S, et al. The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting. Leukemia 2015; 29: 356–8.
Malavasi F, Deaglio S, Damle R, et al. CD38 and chronic lymphocytic leukemia: a decade later. Blood 2011; 118: 3470–8.
Vaisitti T, Aydin S, Rossi D, et al. CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells. Leukemia 2010; 24: 958–9.
Buggins AG, Levi A, Gohil S, et al. Evidence for a macromolecular complex in poor prognosis CLL that contains CD38, CD49d, CD44 and MMP-9. Br J Haematol 2011; 154: 216–22.
Scielzo C, Apollonio B, Scarfo L, et al. The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia. Leukemia 2011; 25: 1760–7.
Lapalombella R, Yeh YY, Wang L, et al. Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals. Cancer Cell 2012; 21: 694–708.
Gary-Gouy H, Bruhns P, Schmitt C, et al. The pseudo-immunoreceptor tyrosine-based activation motif of CD5 mediates its inhibitory action on B-cell receptor signaling. J Biol Chem 2000; 275: 548–56.
Friedman DR, Guadalupe E, Volkheimer A, et al. Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling. Br J Haematol 2018; 183: 747–54.
Pavlasova G, Borsky M, Svobodova V, et al. Rituximab primarily targets an intra-clonal BCR signaling proficient CLL subpopulation characterized by high CD20 levels. Leukemia 2018; 32: 2028–31.
Bologna C, Buonincontri R, Serra S, et al. SLAMF1 regulation of chemotaxis and autophagy determines CLL patient response. J Clin Invest 2016; 126: 181–94.
Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016; 127: 303–9.
Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer J 2018; 8: 93.
Pozzo F, Bittolo T, Arruga F, et al. NOTCH1 mutations associate with low CD20 level in chronic lymphocytic leukemia: evidence for a NOTCH1 mutation-driven epigenetic dysregulation. Leukemia 2016; 30: 182–9.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Experimental Oncology
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
