Prognostic Value of the PRAME Gene Expression in T-Cell Lymphoproliferative Disorders

EA Penskaya1, VA Misyurin2, AE Misyurina1, SK Kravchenko1, LG Gorenkova1, LV Plastinina1, VV Tikhonova2, YuP Finashutina2, NA Lyzhko2, NN Kasatkina2, LA Kesaeva2, ON Solopova2, AV Misyurin2

1 National Medical Hematology Research Center, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vsevolod Andreevich Misyurin, PhD in Biology, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(985)436-30-19; e-mail: vsevolod.misyurin@gmail.com

For citation: Penskaya EA, Misyurin VA, Misyurina AE, et al. Prognostic Value of the PRAME Gene Expression in T-Cell Lymphoproliferative Disorders. Clinical oncohematology. 2019;12(1):73–78.

DOI: 10.21320/2500-2139-2019-12-1-73-78


ABSTRACT

Background. T-cell lymphomas (T-CL) represent a heterogeneous group of malignant lymphoproliferative disorders characterized by unfavorable prognosis. The cancer-testis PRAME gene is notable for its spontaneous expression in transformed cells as observed in solid tumors, B-cell lymphoproliferative and chronic myeloproliferative diseases. Activity and clinical significance of PRAME in T-CL was not studied before, which determines the relevance and provides ground for the present trial.

Aim. To assess the clinical significance of the PRAME gene expression in T-CL.

Materials & Methods. PRAME gene expression level was measured in samples of lymph nodes, blood, and bone marrow from 35 T-CL patients. Among them 3 patients received allogeneic hematopoietic stem cell transplantation, and 6 patients received autologous hematopoietic stem cell transplantation. A correlation was established between the PRAME expression in bone marrow and peripheral blood with morphological markers of disseminated disease with bone marrow lesions and leukemic blood. PRAME expression level was correlated with survival parameters and tumor proliferative activity (Ki-67).

Results. PRAME activity was observed in 21 (60 %) patients. PRAME hyperexpression is associated with advanced stages of disease (= 0.0734), bone marrow lesions (= 0.0289), leukemic blood (= 0.0187), worsening of the overall survival (OS) (p = 0.0787) and event-free survival (EFS) (p = 0.7185), also after hematopoietic stem cell transplantation (= 0.2661 for OS and = 0.0452 for EFS), and with a high Ki-67 expression level (= 0.0155).

Conclusion. PRAME expression in T-CL is often observed and related with unfavorable clinical prognosis.

Keywords: PRAME, T-cell lymphoproliferative disorders, prognostic value.

Received: April 24, 2018

Accepted: December 27, 2018

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Theory and Practice of Immunotherapy Directed against the PRAME Antigen

VA Misyurin

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vsevolod Andreevich Misyurin, PhD in Biology, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(985)4363019; e-mail: vsevolod.misyurin@gmail.com

For citation: Misyurin VA. Theory and Practice of Immunotherapy Directed against the PRAME Antigen. Clinical oncohematology. 2018;11(2):138–49.

DOI: 10.21320/2500-2139-2018-11-2-138-149


ABSTRACT

The preferentially expressed antigen of melanoma (PRAME) is a significant target for monoclonal antibodies and an oncospecific marker known for its activity on all the tumor cell differentiation stages and its eliciting of a spontaneous T-cell response. Since PRAME protein is active in approximately every second patient with solid tumors and oncohematological diseases, anti-PRAME immunotherapy is very promising. In current review the mechanism of spontaneous immune response against PRAME is discussed as well as the role of this antigen in immunosurveillance. The review deals with the PRAME-specific T-cell genesis and risk assessment of immunotherapy directed against PRAME-positive cells. The risks and benefits of various immunotherapy approaches including the use of dendritic cell vaccines, PRAME vaccination, development of specific T-cells, and development of specific monoclonal antibodies were analysed. Possible causes of treatment failure are analysed, and methods of overcoming them are suggested. The literature search in the Pubmed, Scopus, and eLibrary databases, with the use of “PRAME” as a keyword was performed. Only publications related to various aspects of immunotherapy and anti-PRAME-specific agents were included in the review.

Keywords: PRAME, immunotherapy, dendritic cell vaccines, peptide vaccines, T-cell vaccines, therapeutic antibodies.

Received: December 19, 2017

Accepted: February 5, 2018

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Clinical Significance of the PRAME Gene Expression in Oncohematological Diseases

VA Misyurin

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vsevolod Andreevich Misyurin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(985)436-30-19; e-mail: vsevolod.misyurin@gmail.com

For citation: Misyurin AV. Clinical Significance of the PRAME Gene Expression in Oncohematological Diseases. Clinical oncohematology. 2018;11(1):26–33.

DOI: 10.21320/2500-2139-2018-11-1-26-33


ABSTRACT

Although the PRAME activity was first discovered in solid tumors, this gene is very frequently expressed in oncohematological diseases. PRAME can be regarded as a reliable biomarker of tumor cells. Determination of PRAME transcripts is used in residual disease monitoring and molecular relapse diagnostics. Experimentation with PRAME expressing lines of leukemia cells yielded controversial results. Therefore, it is hardly possible to estimate the prognostic value of PRAME activity in oncohematological diseases. In chronic myeloproliferative disease and chronic myeloid leukemia, however, PRAME activity proves to be a predictor of negative prognosis, and on the contrary, it can be regarded as a positive prognostic factor in acute myeloid or lymphoid leukemia. Despite many clinical studies prognostic value of PRAME expression in some diseases requires further investigation. The present literature review contains the data concerning PRAME expression in oncohematological diseases.

Keywords: PRAME, leukemia, lymphoma, prognosis.

Received: September 14, 2017

Accepted: December 2, 2017

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New molecular markers of CML progression

V.A. Misyurin1,2, A.V. Misyurin1,2, L.A. Kesayeva1,2, Yu.P. Finashutina1,2, Ye.N. Misyurina2, I.N. Soldatova1,2, A.A. Krutov2, N.A. Lyzhko1,2, T.V. Akhlynina1,2, A.Ye. Lukina3, T.I. Kolosheynova3, N.V. Novitskaya1, Ye.G. Arshanskaya4, Ye.G. Ovsyannikova5, R.A. Golubenko6, V.A. Lapin7, T.I. Pospelova8, V.A. Tumakov9, and A.Yu. Baryshnikov1

1 N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation

2 GeneTechnology Medical Center, Moscow, Russian Federation

3 Hematology Research Center, RF Ministry of Health, Moscow, Russian Federation

4 Moscow Hematological City Center, S.P. Botkin City Clinical Hospital, Moscow, Russian Federation

5 Astrakhan State Medical Academy, Astrakhan, Russian Federation

6 Orel Regional Clinical Hospital, Orel, Russian Federation

7 Hematological Center, Yaroslavl City Clinical Hospital #1, Yaroslavl, Russian Federation

8 Novosibirsk State Medical University, Novosibirsk, Russian Federation

9 Ivanovo Regional Clinical Hospital #1, Ivanovo, Russian Federation


ABSTRACT

In the contrast to Ph’-negative chronic myeloproliferative disorders (cMPD), chronic myelogenous leukemia (CML) is prone to rather early transformation into the later stage disease, known as the acceleration phase (AP) and blast crisis (BC). Myeloproliferative disorders are termed myeloproliferative neoplasms in the WHO classification, 2008. Molecular mechanisms underlying CML progression are unclear and still being studied. Recently, it was shown that progression of some malignancies was associated with activation and hyperexpression of some genes from the cancer-testis (CT) family. In this study, we evaluated the gene expression profile of CT genes (GAGE1, NY-ESO-1, MAGEA1, SCP1, SEMG1, SPANXA1, SSX1 and PRAME) in the blood of patients with initially diagnosed cMPD, as well as in the blood and bone marrow of CML patients in CP, AP and BC. It was found that activation of these eight CT genes expression was strongly correlated with CML progression to AP and BP. These data suggest that at least some of CT genes can be involved in CML evolution towards the terminal phases. Expression of these genes can be used as an early molecular predictor of CML progression to AP and BC.


Keywords: cancer-testis genes, PRAME, gene expression, chronic myelogenous leukemia, chronic myeloproliferative diseases

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