Dot1L is a Lineage-Specific Tumor Suppressor in Melanocyte
Abstract
This study will address a question with clinical relevance and in an important problem relevant to the Fiscal Year 2014 (FY14) Peer Reviewed Cancer Research Program Topic Areas: Melanoma, and the FY14 Military Relevance Focus Areas: Assessment of militarily relevant risk factors (e.g., environmental carcinogens, UV) associated with the susceptibility, early detection, progression, and treatment of cancer (melanoma). Identification of novel genetic drivers of melanomagenesis may lead to discoveries of new drug targets and the subsequent development of new therapeutic strategies to combat melanoma. To identify such cancer drivers, we analyzed all of the melanoma data available from The Cancer Genome Atlas (TCGA), National Institutes of Health. Interestingly, we found that 5.9% of melanoma has Dot1L mutations. This is further confirmed in the Broad Institute Database, in which 9.6% of melanoma has Dot1L mutations. Notably, 83.9% of mutations are C-T or CC-TT UV signature mutations, and 45.2% of mutations are loss of heterozygosity (LOH) silent mutations. Furthermore, Dot1L mutations have been identified in four melanoma families in UK (personal communication with Dr. David Adam, Wellcom Trust Sanger Institute, UK). These results suggest a tumor suppressor role for Dot1L in melanomagenesis. Given the fact that eukaryotic DNA is wrapped around a histone octamer to form the nucleosome, it is not surprising that alterations in the function of histone-modifying complexes disrupt the pattern and levels of histone marks and consequently deregulate the control of chromatin-based processes. These changes ultimately lead to the oncogenic transformation and the development of cancer. As a histone methyltransferase, Dot1L mediates mono-, di-, and trimethylation of H3K79. Dot1L are responsible for catalyzing H3K79 mono-, di-, and trimethylation reaction. Dot1-dependent H3K79 methylation is associated with telomere silencing, meiotic checkpoint controls, DNA repair, modulation of constitutive heterochromatin, and transcriptional activation. Dot1L is an oncogenic factor in in mixed-lineage leukemia (MLL), and targeted inhibiting Dot1L is in clinical trial in patients with MLL. Here we will further define the role of Dot1L in determining the lineage fates of melanocytes and in melanomagenesis using genetically modified human melanocytes and conditional Dot1L knockout mice (Aim 1). We will also determine the role of Dot1L in UV-induced DNA damage/repair and how Dot1L regulates SOX10 signaling to regulate melanocyte viability (Aim 2). We postulate that the melanocyte lineage specific tumor suppressor Dot1L functions to regulate SOX10 signaling pathway and DNA repair, contributing to UVR-induced melanomagenesis. The proposed studies will define whether Dot1L loss of function is a genetic driver in melanomagenesis with implications in both informed regulation of UV exposure and rationalized development of novel melanoma therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510109
Entities
People
- Rutao Cui
Organizations
- Boston University Medical Campus
- United States Army