Expression levels of the apoptosis genes FAS, TNFR2, TRAIL, DR3 and DR4/5 in patients with newly diagnosed chronic lymphatic leukemia before and after treatment with fludarabine, cyclophosphamide and rituximab (FCR)

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Abstract

Background: We have previously shown that the FAS, TNFR2, TRAIL, DR3, DR4/5 gene expression in patients with newly diagnosed chronic lymphoblastic leukemia (CLL) correlates with clinical manifestations of the disease: they are minimal in patients with high activity of the proapoptotic genes and low activity of the apoptosis-inhibiting genes, and advanced in patients with high expression of the anti-apoptotic and low expression of the pro-apoptotic genes.

Aim: To compare the levels of expression of the external apoptosis pathway genes in patients with newly diagnosed CLL before and after chemotherapy with fludarabine, cyclophosphamide and rituximab (FCR), taking into account baseline clinical data and the response to treatment.

Materials and methods: This prospective one-center cohort study included 23 patients with newly diagnosed CLL, who underwent clinical and diagnostic assessments and treatment from November 2014 to December 2017. Immunophenotyping of peripheral blood lymphocytes for CLL diagnosis was done by fourcolor flow cytometry. Expression of the external apoptosis pathway genes was assessed by realtime reverse transcriptase polymerase chain reaction. All patients were treated with a standard FCR regimen with subsequent maintenance treatment with rituximab.

Results: There were more men (n = 16) than women among our 23 CLL patients. Median age was 64 years (range, from 47 to 77 years). Sixteen (16) patients had CLL Rai Grade I and II, and 7 patients had CLL Grades III and IV. For convenience of analysis, all patients were divided into two groups depending on the FAS gene expression. At baseline, the patients with high FAS expression had higher TNFR2 (p < 0.0015) and TRAIL (p < 0.0053) expression levels. Before FCR therapy, the patients with low FAS expression had higher lymphocyte counts (р = 0.0016) and lower erythrocyte counts (р = 0.0159). At baseline, there were more Grade I and II patients in the group with higher FAS expression (р = 0.0205). At day 3 after the end of a four day FCR cycle, there was an increase only of the FAS (p = 0.0025) and TRAIL (p = 0.0045) expression. After the completion of the first FCR cycle, lymphocyte counts in the patients with low FAS expression decreased earlier than those in the patients with high FAS expression (p = 0.0019). After six FCR cycles, complete or partial remission was obtained in 82% (19/23) of the patients. The patients with high FAS expression had higher complete remission rate (р = 0.026). No adverse events related to FCR were registered.

Conclusion: The external apoptosis pathway genes are one of the key factors of the tumor progression in CLL. Our data on the effect of FCR therapy on the FAS and TRAIL gene expression make it possible to consider them as a target for this combination regimen and may become the rationale to develop new pharmaceutical molecules.

About the authors

S. G. Zakharov

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: hematologymoniki@mail.ru

Sergey G. Zakharov – MD, Research Fellow, Department of Clinical Hematology and Immunotherapy

61/2 Shchepkina ul., Moscow, 129110

Россия

A. K. Golenkov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Anatoliy K. Golenkov – MD, PhD, Professor, Head of the Department of Clinical Hematology and Immunotherapy 

61/2 Shchepkina ul., Moscow, 129110

Россия

V. A. Misyurin

N.N. Blokhin National Medical Research Centre of Oncology

Email: fake@neicon.ru

Vsevolod A. Misyurin – PhD in Biology, Senior Research Fellow, Laboratory of Experimental Diagnostics and Biotherapy of Tumors 

24 Kashirskoe shosse, Moscow, 115478

Россия

E. V. Kataeva

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Elena V. Kataeva – MD, PhD, Senior Research Fellow, Department of Clinical Hematology and Immunotherapy 

61/2 Shchepkina ul., Moscow, 129110

Россия

M. A. Baryshnikova

N.N. Blokhin National Medical Research Centre of Oncology

Email: fake@neicon.ru

Mariya A. Baryshnikova – PhD in Pharmacology, Head of the Laboratory of Experimental Diagnostics and Biotherapy of Tumors 

24 Kashirskoe shosse, Moscow, 115478

Россия

Yu. Yu. Chuksina

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Yuliya Yu. Chuksina – MD, PhD, Senior Research Fellow, Department of Clinical Hematology and Immunotherapy 

61/2 Shchepkina ul., Moscow, 129110

Россия

T. A. Mitina

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Tat'yana A. Mitina – MD, PhD, Senior Research Fellow, Department of Clinical Hematology and Immunotherapy 

61/2 Shchepkina ul., Moscow, 129110

Россия

E. V. Trifonova

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Elena V. Trifonova – MD, PhD, Senior Research Fellow, Department of Clinical Hematology and Immunotherapy 

61/2 Shchepkina ul., Moscow, 129110

Россия

L. L. Vysotskaya

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Lyudmila L. Vysotskaya – MD, PhD, Research Fellow, Department of Clinical Hematology and Immunotherapy 

61/2 Shchepkina ul., Moscow, 129110

Россия

Yu. B. Chernykh

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Yuliya B. Chernykh – MD, PhD, Senior Research Fellow, Department of Clinical Hematology and Immunotherapy 

61/2 Shchepkina ul., Moscow, 129110

Россия

E. F. Klinushkina

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Elena F. Klinushkina – Junior Research Fellow, Department of Clinical Hematology and Immunotherapy 

61/2 Shchepkina ul., Moscow, 129110

Россия

K. A. Belousov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Kirill A. Belousov – Research Fellow, Department of Clinical Hematology and Immunotherapy

61/2 Shchepkina ul., Moscow, 129110

Россия

Yu. P. Finashutina

N.N. Blokhin National Medical Research Centre of Oncology

Email: fake@neicon.ru

Yuliya P. Finashutina – Research Fellow, Laboratory of Recombinant Tumor Antigens

24 Kashirskoe shosse, Moscow, 115478

Россия

A. V. Misyurin

N.N. Blokhin National Medical Research Centre of Oncology

Email: fake@neicon.ru

Andrey V. Misyurin – PhD, ScD in Biology, Head of the Laboratory of Recombinant Tumor Antigens 

24 Kashirskoe shosse, Moscow, 115478

Россия

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Copyright (c) 2018 Zakharov S.G., Golenkov A.K., Misyurin V.A., Kataeva E.V., Baryshnikova M.A., Chuksina Y.Y., Mitina T.A., Trifonova E.V., Vysotskaya L.L., Chernykh Y.B., Klinushkina E.F., Belousov K.A., Finashutina Y.P., Misyurin A.V.

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