Epigenetic mechanisms play an important role in cancer initiation and progression through modulation of gene expression. Cutaneous T cell lymphoma (CTCL) is defined by infiltration of activated and malignant CD4+ T- cells in the skin. The molecular mechanisms underlying the proliferation of neoplastic CD4+ T-cells in CTCL are not fully understood, but involve epigenetic silencing of multiple tumor suppressor genes. Sterile alpha motif (SAM) and HD domain-containing protein 1 (SAMHD1) is the first identified mammalian triphosphohydrolase that hydrolyzes cellular deoxynucleoside triphosphates (dNTPs). By depleting intracellular dNTPs required for retroviral replication, SAMHD1 blocks retroviral infection in resting CD4+ T-cells and myeloid cells. These cells express high levels of SAMHD1 protein and have 6- to 100-fold lower levels of intracellular dNTPs compared to activated CD4+ T-cells, while several leukemia and lymphoma CD4+ T-cell lines lack SAMHD1 protein expression and have increased dNTP levels. The goal of this project is to better understand the mechanisms and pathogenic consequences of epigenetic silencing of SAMHD1 in CTCL, which may aid in developing novel therapeutic approaches to treat CTCL. A key question is whether CD4+ T-cells from CTCL patients down- regulate or lack SAMHD1 expression to maintain high levels of intracellular dNTPs and support efficient DNA replication and uncontrolled cell growth. Our preliminary results suggest that human SAMHD1 may function as a tumor suppressor in CTCL. Interestingly, we observed 3-fold lower SAMHD1 mRNA levels in peripheral blood mononuclear cells from 9 CTCL patients compared to 14 healthy donors (p=0.0013), indicating that SAMHD1 expression is down-regulated in CTCL patients. We also found that epigenetic modification of the SAMHD1 gene is critical for silencing of SAMHD1 expression, which may in turn regulate DNA replication and cell growth of malignant CD4+ T-cells. Thus, we hypothesize that SAMHD1 functions as a tumor suppressor, and that epigenetic silencing of SAMHD1 expression in malignant CD4+ T-cells leads to increased intracellular dNTPs and contributes to uncontrolled T-cell growth in CTCL. To test this hypothesis, we propose two specific aims:
Aim 1. To determine the correlation between SAMHD1 expression and dNTP levels in CD4+ T-cells from 50 patients with CTCL;
and Aim 2. To investigate the mechanisms of epigenetic silencing of SAMHD1 in malignant CD4+ T-cells and to validate the results using a CTCL mouse model and a SAMHD1 knockout mouse model. Achieving our goals will provide critical knowledge into a novel mechanism that regulates dNTP metabolism in malignant CD4+ T-cells, which will facilitate the development of more effective drugs against CTCL and other T-cell lymphomas. Discovery of the mechanisms leading to loss of SAMHD1 protein expression could support the development of strategies to re-induce SAMHD1 gene expression as a new therapeutic modality in CTCL. SAMHD1's function as a novel tumor suppressor may also be important in other types of cancer and have a broader impact beyond CTCL.
Lymphoma is the most common blood cancer and the third most common cancer of childhood. According to the National Cancer Institute, it was estimated that 79,190 people were diagnosed with lymphoma and 20,130 people died of lymphoma in the US in 2012. The goal of this project is to better understand the novel role of the host enzyme SAMHD1 as a tumor suppressor, which will aid in developing new therapeutic approaches to treat lymphomas and other cancers.
|Kenney, Adam D; Dowdle, James A; Bozzacco, Leonia et al. (2017) Human Genetic Determinants of Viral Diseases. Annu Rev Genet 51:241-263|
|Kodigepalli, Karthik M; Li, Minghua; Liu, Shan-Lu et al. (2017) Exogenous expression of SAMHD1 inhibits proliferation and induces apoptosis in cutaneous T-cell lymphoma-derived HuT78 cells. Cell Cycle 16:179-188|
|Kohnken, Rebecca; Kodigepalli, Karthik M; Mishra, Anjali et al. (2017) MicroRNA-181 contributes to downregulation of SAMHD1 expression in CD4+ T-cells derived from Sèzary syndrome patients. Leuk Res 52:58-66|
|Li, Chuan; Wang, Hai-Bo; Kuang, Wen-Dong et al. (2017) Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4+ T Cells. J Virol 91:|
|Antonucci, Jenna M; St Gelais, Corine; de Silva, Suresh et al. (2016) SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity. Nat Med 22:1072-1074|
|Tirumuru, Nagaraja; Zhao, Boxuan Simen; Lu, Wuxun et al. (2016) N(6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. Elife 5:|
|Wang, Feifei; St Gelais, Corine; de Silva, Suresh et al. (2016) Phosphorylation of mouse SAMHD1 regulates its restriction of human immunodeficiency virus type 1 infection, but not murine leukemia virus infection. Virology 487:273-84|
|St Gelais, Corine; Kim, Sun Hee; Ding, Lingmei et al. (2016) A Putative Cyclin-binding Motif in Human SAMHD1 Contributes to Protein Phosphorylation, Localization, and Stability. J Biol Chem 291:26332-26342|
|Bonifati, Serena; Daly, Michele B; St Gelais, Corine et al. (2016) SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells. Virology 495:92-100|
|Kohnken, Rebecca; Kodigepalli, Karthik M; Wu, Li (2015) Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications. Mol Cancer 14:176|
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