SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP

Abstract

Highlights d SAMHD1-deficient cells die upon exposure to deoxyguanosine (dG) d dG induces apoptosis in cells, including cancer cells, lacking SAMHD1 d PNP-inhibitors such as forodesine and dG synergistically trigger cell death d dG and forodesine kill mutated leukemic cells without SAMHD1 expression

SAMHD1mutations in mantle cell lymphoma are recurrent and conferin vitroresistance to nucleoside analogues

“…The observation that AML, T-PLL and MCL with altered SAMHD1 expression (either by deletion, mutation or other mechanisms) respond differently might therefore be explained by differences in cell type and by different functional effect depending on type of alteration. A recent article by Davenne and co-workers[15] reported functional and pharmacological effects of SAMHD1 depletion in CLL cells, notably identifying forodesine as a potent agent in cells lacking SAMHD1 and elucidating the underlying mechanism. These results raise the possibility of a targeted use of forodesine in MCL carrying disrupting SAMHD1 mutations, further highlighting the potential of SAMHD1 as a predictive biomarker.…”

PNP inhibitors selectively kill cancer cells lacking SAMHD1

“…Using cell viability analysis and mass cytometry, we found that leukemic cells from patients with SAMHD1 loss-of-function mutations were killed by forodesine and dG (Figure 1). 2 In contrast, normal PBMCs and leukemic cells with SAMHD1 survived.…”

“…However, our studies led to a very different observation: cells without SAMHD1 started dying after feeding with dNs, whereas cells with SAMHD1 were unaffected. 2 Amongst the four dNs, deoxyguanosine (dG) showed the highest toxicity. dG was converted intracellularly to deoxyguanosine triphosphate (dGTP) and triggered apoptosis in a variety of SAMHD1-deficient cell types and cell lines from human and mouse, but not in SAMHD1-sufficient cells.…”

“…We concluded that SAMHD1 plays an important role in safeguarding cells against imbalances in dNTP levels ( Figure 1). 2 Acquired mutations in SAMHD1 were identified in different types of cancer, including in some patients with refractory chronic lymphocytic leukemia (CLL), 3 as well as in lung and colon cancer. These mutations typically result in a loss of SAMHD1 protein expression.…”

“…We concluded that SAMHD1 plays an important role in safeguarding cells against imbalances in dNTP levels ( Figure 1 ). 2

Figure 1. SAM and HD domain-containing protein 1 (SAMHD1)-deficient cells are susceptible to cell death triggered by deoxyribonucleoside triphosphate (dNTP) imbalances

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