Clinical and biological impact of SAMHD1 expression in mantle cell lymphoma

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).

SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma

“…However, the correlation was mainly driven by lower SAMHD1 expression in nonnodal MCL (nnMCL) ( supplemental Figure 10 C) and lost when restricting the analysis to cMCL ( supplemental Figure 10 B). Consistently, silencing of SOX11 in SOX11 + MCL cell lines 19 or induction of SOX11 in SOX11 − JVM-2 ( Figure 3 F; supplemental Figure 10 D) did not affect SAMHD1 expression. Analyses of SAMHD1 histone marks and DNA methylation together with SAMHD1 messenger RNA expression in 5 published MCL cases (2 cMCL and 3 nnMCL) in comparison with normal B cells 43 , 44 did not further reveal evidence of epigenetic regulation of differential SAMHD1 expression in MCL ( supplemental Figure 10 E).…”

“…We have previously shown that there is a weak positive correlation of SOX11 and SAMHD1 expression based on immunohistochemistry (N = 62; Spearman correlation coefficient, 0.27; P = .036). 19 To further investigate this, we analyzed gene expression data of 44 previously published MCL cases 43 and confirmed a positive correlation of SAMHD1 and SOX11 expression (Spearman rank correlation R = 0.37; P = .013; supplemental Figure 10 A). However, the correlation was mainly driven by lower SAMHD1 expression in nonnodal MCL (nnMCL) ( supplemental Figure 10 C) and lost when restricting the analysis to cMCL ( supplemental Figure 10 B).…”

“…Cryo-preserved cells taken from diagnostic samples of patients with MCL from our recent study 19 were used for SOX11-SAMHD1 colocalization by proximity ligation assay (PLA). Three samples with high lymphoma cell purity (>90% of MCL cells) were selected for ara-C treatment and labeled as PS1-3.…”

“…Protein expression was measured by performing western blotting using total cell lysates from siRNA-transfected, Vpx-treated, SOX11-induced, or ara-C–treated cell lines as previously described. 19 Blots were developed using Western Lightning Plus ECL, Enhanced Chemiluminescence Substrate (NEL104001EA), and visualization and semiquantification were performed using a LiCOR machine and Odyssey software, respectively. For reprobing purposes, membranes were stripped using Restore Western Blot Stripping Buffer (Thermo Fisher, catalog no.…”

“… 14 , 15 Accordingly, clinical outcome in ara-C–treated patients with AML is negatively correlated with SAMHD1 expression levels. 15 , 16 , 17 Contrary to AML, no clear correlation of SAMHD1 expression and ara-C responses could be identified in MCL, 18 , 19 suggesting the existence of SAMHD1-modulating factors in MCL.…”