doi:10.1111/ejh.12574
European Journal of Haematology 95 (487–488)
EDITORIAL
Is TCL1 overexpression a good or a bad player in mantle cell lymphoma? Silvia Bea, Estella Matutes diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Hematopathology Unit, Hospital Clınic and Institut d’Investigacions Biome
The T-cell leukemia/lymphoma (TCL1) oncoprotein is encoded by the TCL1 proto-oncogene located at 14q32.13. TCL1 acts as a regulator of AKT and enhances its kinase activity leading to its activation. The TCL1 protein has been shown to be expressed at low levels in normal B- and T-cell precursors and na€ıve mature B cells but not in mature T lymphocytes. Dysregulation of TCL1 leading to increased cell proliferation and survival may occur by rearrangements of the gene as in the case of T-cell prolymphocytic leukemia or by amplification or overexpression. Cells from the majority of mature B-cell malignancies appear to show high levels of TCL1, with a degree of variability among the tumor samples within a given disease, except in Burkitt’s lymphoma (1). Few reports have indicated that overexpression of TCL1 protein and mRNA correlate with relapse and lower 5-yr overall survival (OS) in diffuse large B-cell lymphoma, independently of the international prognostic index (IPI) scores (2), whereas in chronic lymphocytic leukemia, it has been associated with aggressive disease features and shorter progression-free survival (1, 3) In this issue, Shin et al. (4) document the prognostic impact of TCL1 expression in a cohort of 144 patients with mantle cell lymphoma (MCL) in which TCL1 assessment was available by an automatic immunostaining in tissue microarray sections. The majority of patients had advanced stage and aggressive disease, while less than 5% had indolent MCL. High TCL1 expression was defined by the presence of more than 40% of lymphoid cells expressing the protein with moderate to strong intensity in the nuclei and/or cytoplasm. Unexpectedly, low TCL1 expression correlated with blastoid morphology. At a median follow-up of 30.3 months, multivariate analysis showed that low TCL1 expression together with high-risk mantle cell lymphoma IPI (MIPI) and anemia (Hb < 12 gr/dL) were independent adverse prognostic factors for OS. The poorer OS in the patients with low TCL1 expression was shown also in the subgroup of patients with low/intermediate MIPI scores. However, low TCL1 expression was not associated with poorer PFS. The results from this study clearly contradict those from another that showed that high TCL1 expression
Correspondence Estella Matutes, MD, PhD, Hematopathology Unit, Hospital Clinic. Villarroel 170, 08036 Barcelona, Spain. Tel: +34663109312; Fax: +34932275572; e-mail: [email protected]
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
was an adverse prognostic factor in 64 newly diagnosed patients with MCL (1). This discrepancy may well reflect methodological differences to consider a case TCL1 positive or negative because the definition in the study of Aggarwal et al. was based on a quantitative and qualitative assessment and compared OS in patients with the lower quartile of TCL1 expression with those with the 3 upper quartiles. Caveats of both two studies are their retrospective nature and, at least in Shin et al. study, the variability of possibly suboptimal therapies received by the patients, with almost half of them not receiving immunochemotherapy and up to 19% ‘conservative’ treatments. The treatment modalities were not specified in the study of Aggarwal et al. MCL is a rare aggressive mature lymphoid neoplasm that still remains incurable although the outlook has improved over the last decades. So far, the MIPI scores developed in 2008 have shown reliably to stratify the patients in risk groups with different OS and PFS. This has been validated in large prospective randomized or non-randomized trials in which the patients with advanced disease received optimal standard treatments such as rituximab-based treatment and autologous stem cell transplantation. The need to introduce biomarkers in combination with clinical parameters in the prognostic scenario of MCL has already been considered for several years. The first of these biomarkers was the measurement of the cell proliferation level by immunostaining with Ki-67. The presence of a high percentage of Ki-67+ cells in the tissues was shown to have a negative impact on PFS and OS. Despite of the pitfalls in the quantification of cell proliferation due to the lack of reproducibility, the addition of Ki-67 levels into the MIPI scores, designated biological MIPI (MIPIb), has further improved the discrimination between high-risk versus low-/intermediate-risk patients with MCL. Furthermore, the prognostic impact of SOX11 expression on MCL is still contradictory as to whether is an adverse or favorable prognostic factor for OS. The apparent conflicting results may well be related to the heterogeneity of treatments received by the patients in these studies, as well as differences in the sample population of MCL analyzed, that included indolent and classical cases in some studies or only classical MCL in others. Therefore, it may be that SOX11 expression, rather than being by itself a prognostic marker in aggressive MCL, has a major role in the diagnosis of cyclin D1-negative MCL cases and also in identifying a particular biological and clinical subgroup of
487
Editorial
non-aggressive indolent MCL with mutated IGHV genes (5). In our series of 47 leukemic MCL analyzed by gene expression profiling (5), there was a significant positive correlation between high SOX11 and TCL1 levels. Moreover, a comparison on outcome of patients with low and high expression of TCL1 (upper quartile) showed that high TCL1 was an adverse prognostic factor for OS (P = 0.041, unpublished data). However, when the analysis was confined to the SOX11-positive MCL, there was no significant difference, suggesting that SOX11 expression rather than TCL1 levels may be responsible for the shorter OS. In summary, with the present available data, the prognostic impact of TCL1 on MCL is still uncertain. Although identification of prognostic biomarkers, such as TCL1 or SOX11, in cohort populations of aggressive MCL is of great value, they need to be validated in prospective trials using optimal treatments and with standardization of the methodology, before their introduction in the prognostic scenario of MCL in the clinical practice
488
References 1. Aggarwal M, Villuendas R, Gomez G, et al. TCL1A expression delineates biological and clinical variability in B-cell lymphoma. Mod Pathol 2009;22:206–15. 2. Ramuz O, Bouabdallah R, Devilard E, et al. Identification of TCL1A as an immunohistochemical marker of adverse outcome in diffuse large B-cell lymphomas. Int J Oncol 2005;26:151–7. 3. Herling M, Patel KA, Weit N, et al. High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia. Blood 2009;114:4675–86. 4. Shin S-J, Roh J, Cha HJ, et al. TCL1 expression predicts overall survival in patients with mantle cell lymphoma. Eur J Haematol, in press. 5. Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biological and clinical features. Cancer Res 2012;72:5307–16.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
European Journal of Haematology 95 (487–488)
EDITORIAL
Is TCL1 overexpression a good or a bad player in mantle cell lymphoma? Silvia Bea, Estella Matutes diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Hematopathology Unit, Hospital Clınic and Institut d’Investigacions Biome
The T-cell leukemia/lymphoma (TCL1) oncoprotein is encoded by the TCL1 proto-oncogene located at 14q32.13. TCL1 acts as a regulator of AKT and enhances its kinase activity leading to its activation. The TCL1 protein has been shown to be expressed at low levels in normal B- and T-cell precursors and na€ıve mature B cells but not in mature T lymphocytes. Dysregulation of TCL1 leading to increased cell proliferation and survival may occur by rearrangements of the gene as in the case of T-cell prolymphocytic leukemia or by amplification or overexpression. Cells from the majority of mature B-cell malignancies appear to show high levels of TCL1, with a degree of variability among the tumor samples within a given disease, except in Burkitt’s lymphoma (1). Few reports have indicated that overexpression of TCL1 protein and mRNA correlate with relapse and lower 5-yr overall survival (OS) in diffuse large B-cell lymphoma, independently of the international prognostic index (IPI) scores (2), whereas in chronic lymphocytic leukemia, it has been associated with aggressive disease features and shorter progression-free survival (1, 3) In this issue, Shin et al. (4) document the prognostic impact of TCL1 expression in a cohort of 144 patients with mantle cell lymphoma (MCL) in which TCL1 assessment was available by an automatic immunostaining in tissue microarray sections. The majority of patients had advanced stage and aggressive disease, while less than 5% had indolent MCL. High TCL1 expression was defined by the presence of more than 40% of lymphoid cells expressing the protein with moderate to strong intensity in the nuclei and/or cytoplasm. Unexpectedly, low TCL1 expression correlated with blastoid morphology. At a median follow-up of 30.3 months, multivariate analysis showed that low TCL1 expression together with high-risk mantle cell lymphoma IPI (MIPI) and anemia (Hb < 12 gr/dL) were independent adverse prognostic factors for OS. The poorer OS in the patients with low TCL1 expression was shown also in the subgroup of patients with low/intermediate MIPI scores. However, low TCL1 expression was not associated with poorer PFS. The results from this study clearly contradict those from another that showed that high TCL1 expression
Correspondence Estella Matutes, MD, PhD, Hematopathology Unit, Hospital Clinic. Villarroel 170, 08036 Barcelona, Spain. Tel: +34663109312; Fax: +34932275572; e-mail: [email protected]
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
was an adverse prognostic factor in 64 newly diagnosed patients with MCL (1). This discrepancy may well reflect methodological differences to consider a case TCL1 positive or negative because the definition in the study of Aggarwal et al. was based on a quantitative and qualitative assessment and compared OS in patients with the lower quartile of TCL1 expression with those with the 3 upper quartiles. Caveats of both two studies are their retrospective nature and, at least in Shin et al. study, the variability of possibly suboptimal therapies received by the patients, with almost half of them not receiving immunochemotherapy and up to 19% ‘conservative’ treatments. The treatment modalities were not specified in the study of Aggarwal et al. MCL is a rare aggressive mature lymphoid neoplasm that still remains incurable although the outlook has improved over the last decades. So far, the MIPI scores developed in 2008 have shown reliably to stratify the patients in risk groups with different OS and PFS. This has been validated in large prospective randomized or non-randomized trials in which the patients with advanced disease received optimal standard treatments such as rituximab-based treatment and autologous stem cell transplantation. The need to introduce biomarkers in combination with clinical parameters in the prognostic scenario of MCL has already been considered for several years. The first of these biomarkers was the measurement of the cell proliferation level by immunostaining with Ki-67. The presence of a high percentage of Ki-67+ cells in the tissues was shown to have a negative impact on PFS and OS. Despite of the pitfalls in the quantification of cell proliferation due to the lack of reproducibility, the addition of Ki-67 levels into the MIPI scores, designated biological MIPI (MIPIb), has further improved the discrimination between high-risk versus low-/intermediate-risk patients with MCL. Furthermore, the prognostic impact of SOX11 expression on MCL is still contradictory as to whether is an adverse or favorable prognostic factor for OS. The apparent conflicting results may well be related to the heterogeneity of treatments received by the patients in these studies, as well as differences in the sample population of MCL analyzed, that included indolent and classical cases in some studies or only classical MCL in others. Therefore, it may be that SOX11 expression, rather than being by itself a prognostic marker in aggressive MCL, has a major role in the diagnosis of cyclin D1-negative MCL cases and also in identifying a particular biological and clinical subgroup of
487
Editorial
non-aggressive indolent MCL with mutated IGHV genes (5). In our series of 47 leukemic MCL analyzed by gene expression profiling (5), there was a significant positive correlation between high SOX11 and TCL1 levels. Moreover, a comparison on outcome of patients with low and high expression of TCL1 (upper quartile) showed that high TCL1 was an adverse prognostic factor for OS (P = 0.041, unpublished data). However, when the analysis was confined to the SOX11-positive MCL, there was no significant difference, suggesting that SOX11 expression rather than TCL1 levels may be responsible for the shorter OS. In summary, with the present available data, the prognostic impact of TCL1 on MCL is still uncertain. Although identification of prognostic biomarkers, such as TCL1 or SOX11, in cohort populations of aggressive MCL is of great value, they need to be validated in prospective trials using optimal treatments and with standardization of the methodology, before their introduction in the prognostic scenario of MCL in the clinical practice
488
References 1. Aggarwal M, Villuendas R, Gomez G, et al. TCL1A expression delineates biological and clinical variability in B-cell lymphoma. Mod Pathol 2009;22:206–15. 2. Ramuz O, Bouabdallah R, Devilard E, et al. Identification of TCL1A as an immunohistochemical marker of adverse outcome in diffuse large B-cell lymphomas. Int J Oncol 2005;26:151–7. 3. Herling M, Patel KA, Weit N, et al. High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia. Blood 2009;114:4675–86. 4. Shin S-J, Roh J, Cha HJ, et al. TCL1 expression predicts overall survival in patients with mantle cell lymphoma. Eur J Haematol, in press. 5. Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biological and clinical features. Cancer Res 2012;72:5307–16.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
