Expression of the novel tumour suppressor sterile alpha motif and HD domain‐containing protein 1 is an independent adverse prognostic factor in classical Hodgkin lymphoma

Abstract

The expression patterns and prognostic significance of sterile alpha motif and HD domain-containing protein 1 (SAMHD1) protein in the neoplastic Hodgkin and Reed Sternberg (HRS) cells of Hodgkin lymphoma (HL) were investigated in a cohort of 154 patients with HL treated with standard regimens. SAMHD1 expression was assessed by immunohistochemistry using diagnostic lymph node biopsies obtained prior to treatment. Using an arbitrary 20% cut-off, SAMHD1 was positive in HRS cells of 48/154 (31Á2%) patients. SAMHD1 expression was not associated with clinicopathologic parameters, such as age, gender, stage or histologic subtype. In 125 patients with a median follow-up of 90 months (7-401 months), SAMHD1 expression in HRS cells significantly correlated with inferior freedom from progression (FFP) (P = 0Á025), disease-specific survival (DSS) (P = 0Á013) and overall survival (OS) (P = 0Á01). Importantly, in multivariate models together with disease stage, histology subtype and type of treatment as covariates, SAMHD1 expression retained an independent significant association with unfavourable FFP (P = 0Á005) as well as DSS (P = 0Á022) and OS (P = 0Á018). These findings uncover the significance of a novel, adverse prognostic factor in HL that may have therapeutic implications since SAMHD1 inhibitors are now available for clinical use.

Multifaceted roles of SAMHD1 in cancer

“…One study detected a SAMHD1 increase upon lung cancer progression [Shang et al, 2018], and the most recent study, correlated the presence of SAMHD1 in Hodgkin lymphoma cells with unfavourable outcome [Xagoraris et al, 2021]. Notably, this study [Xagoraris et al, 2021] even referred to SAMHD1 as “novel tumour suppressor” in the title, although the study rather indicated an oncogenic role of SAMHD1.…”

“…Among the 35 articles that reported on an association between SAMHD1 and cancer, four did not (entirely) support the ‘SAMHD1 is a tumour suppressor’ narrative [Yang et al, 2017; Kodigepalli et al, 2018; Shang et al, 2018; Xagoraris et al, 2021]. One study correlated high SAMHD1 levels with metastasis formation in colorectal cancer [Yang et al, 2017].…”

“…Notably, the title of this study exclusively focused on the inhibitory effects of SAMHD1 on leukaemia cell proliferation and did not mention its role in tumourigenesis [Kodigepalli et al, 2018]. One study detected a SAMHD1 increase upon lung cancer progression [Shang et al, 2018], and the most recent study, correlated the presence of SAMHD1 in Hodgkin lymphoma cells with unfavourable outcome [Xagoraris et al, 2021]. Notably, this study [Xagoraris et al, 2021] even referred to SAMHD1 as “novel tumour suppressor” in the title, although the study rather indicated an oncogenic role of SAMHD1.…”

“…Thus, researchers are more likely to look for data that support their hypothesis and not for those that contradict it. Notably, one study referred to SAMHD1 as "novel tumour suppressor" in the title, although SAMHD1 expression was described as an adverse prognostic factor in Hodgkin lymphoma [Xagoraris et al, 2021].…”

Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells

“…Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleotides and inorganic triphosphate [ 11 , 38 ]. SAMHD1 also inactivates the triphosphorylated forms of some anti-cancer nucleoside analogues [ 13 , 21 , 36 , 39 , 41 , 50 ]. High SAMHD1 levels indicate poor clinical response to nucleoside analogues such as cytarabine, decitabine, and nelarabine in acute myeloid leukaemia (AML), acute lymphoblastic leukaemia, and Hodgkin lymphoma [ 36 , 39 , 41 , 50 ].…”