| 1. |
- Abdelrazak Morsy, Mohammad Hamdy, et al.
(författare)
-
SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma
- 2024
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 143:19, s. 1953-1964
-
Tidskriftsartikel (refereegranskat)abstract
- Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara -C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara -C ef fi cacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMGbox containing protein 11 (SOX11) as a novel direct binding partner and fi rst known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identi fi ed SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar af fi nity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara -C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identi fi ed SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its fi rst known endogenous inhibitor with potentially important implications for clinical therapy strati fi cation.
|
|
| 2. |
- Merrien, Magali, et al.
(författare)
-
Clinical and biological impact of SAMHD1 expression in mantle cell lymphoma
- 2022
-
Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 480:3, s. 655-666
-
Tidskriftsartikel (refereegranskat)abstract
- SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158).
|
|
| 3. |
- Merrien, Magali
(författare)
-
The role of cannabinoid receptors, G alpha z, and B cell receptor in lymphoma pathobiology with focus on chemotaxis
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL) are two incurable B cell malignancies, with an overall survival of 5 to 8 years and 6 to 10 years, respectively. Therapies are available but are often very aggressive, and patients relapse due to minimal residual disease. Minimal residual disease is defined by the presence of few malignant cells that escaped from therapy, mainly due to the survival signals provided by non-malignant cells from the tissue environment, in lymph nodes and in bone marrow. Alternative and targeted therapies are under investigation to increase patient overall survival and to reduce the risks of relapses. However, some patients do not respond to these treatments, as malignant cells develop mechanisms that prevent the drug efficacy. Many factors have already been depicted to contribute to MCL pathogenesis, and in this thesis, a new potential actor in MCL pathobiology is described, the protein G alpha z (Gαz). The gene encoding for Gαz, GNAZ is overexpressed in most MCL cases compared to B lymphocytes from reactive lymph nodes. It was found that GNAZ expression correlates with lymphocytosis, and inversely correlates with the cannabinoid receptor type 1 previously described as a receptor potentially involved in the egress and/or retention of MCL cells within the tissue. Although the downregulation of GNAZ did not affect cell survival, proliferation or chemotaxis in vitro, its potential role in MCL pathobiology is of interest and needs further investigation. Moreover, we characterize a co-culture in vitro system of MCL cell lines with mesenchymal stromal cells that permitted to identify differentially expressed genes between cells from different tissue origin. The JeKo-1 MCL cell line from peripheral blood origin, utilized the BCR signalling pathway to adhere to stromal cells, while the Rec-1 MCL cell line from lymph node origin did not, which conferred resistance to BCR targeted therapies. This system could be useful for testing patient samples to determinate a potential resistance before treatment decision. Finally, the endocannabinoid system has been previously identified as dysregulated in both MCL and CLL. Here, we provide a new role of the endogenous cannabinoid 2-arachidonoylglycerol in chemotaxis of malignant B cells, regulated by both cannabinoid receptors type 1 and type 2. This endocannabinoid did not only induce chemotaxis by itself but also modulated the chemotaxis towards the chemokine CXCL12. In addition, a single administration of the natural cannabinoids, THC and CBD, in lymphoma patients promoted the redistribution of malignant cells from peripheral blood, and also affected non-malignant immune cells in blood. This potential negative effect of cannabinoids on the immune cells should be taken into consideration, knowing that around 25% of
|
|
| 4. |
- Mundt, Filip, et al.
(författare)
-
Expression of GNAZ, encoding the G alpha(z) protein, predicts survival in mantle cell lymphoma
- 2019
-
Ingår i: British Journal of Haematology. - : WILEY. - 0007-1048 .- 1365-2141. ; 185:4, s. 708-712
-
Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL), a malignancy of B-lymphocytes, has a poor prognosis. It is thus necessary to improve the understanding of the pathobiology of MCL and identify factors contributing to its aggressiveness. Our studies, based on Affymetrix data from 17 MCL biopsies, real-time quantitative polymerase chain reaction data from 18 sorted primary MCL cells and 108 MCL biopsies compared to non-malignant tissue, reveals that GNAZ expression predicts poor clinical outcome of MCL patients (Cox regression, P = 0 center dot 014) and lymphocytosis (Mann-Whitney, P = 0 center dot 011). We show that GNAZ translates to G alpha(z) protein - a signalling molecule within the G-protein coupled receptor network. Our findings suggest that GNAZ/G alpha(z) contribute to the MCL pathobiology.
|
|
