Research Highlights

RNA Epigenetics Research
RNA modifications have been shown to play important roles in various fundamental bioprocesses. N6-methyladenosine (m6A) is the most abundant internal modification in messenger RNAs (mRNAs). Such modification mainly occurs at the consensus motif of G[G>A]m6AC[U>A>C]. The Chen laboratory has recently been focusing on studying the functions and the underlying mechanisms of the ‘writers’ (i.e., METTL3 and METTL14 as well as their cofactor, WTAP), ‘erasers’ (e.g., FTO and ALKBH1-5) and ‘readers’ (e.g., YTHDF1-3 and YTHDC1-3) of the m6A modification in various normal biological processes. We are also investigating the pathological roles of these proteins in the pathogenesis (initiation, progression and maintenance) and drug response/resistance of leukemia and other cancers (see Cancer Cell 2017). Genetic knockout mouse models for these genes are being or will be employed in the functional and mechanistic studies.

DNA Epigenetics Research
The Chen laboratory has been working on TET protein-related DNA epigenetics for years. The Ten-eleven translocation (TET) proteins (including TET1/2/3) are a family of methylcytosine dioxygenases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), leading to active or passive DNA demethylation. In contrast to the down-regulation and potential tumor-suppressor roles of all three TET genes reported in various types of solid tumors, as well as the repression and tumor-suppressor role of TET2 observed in hematopoietic malignancies, we have recently shown that TET1 is significantly up-regulated in certain subtypes of acute myeloid leukemia (AML) and plays an essential oncogenic role in leukemogenesis (see PNAS 2013; Cancer Letter 2016; Nature Communications, 2016). Interestingly, TET1 can cooperate with MLL-fusion proteins to promote expression of a set of critical oncogenes such as Hoxa, Meis1, and Pbx3 genes, or cooperate with Polycomb-group proteins to epigenetically repress (likely unrelated to the enzymatic activity of TET1) the transcription of a set of tumor-suppressor genes such as miR-22 (see PNAS 2013; Nature Communications, 2016). We are now systematically investigating the biological functions and the underlying molecular mechanisms of all the three TET genes, individually or in combination, in both normal hematopoiesis and hematopoietic malignancies. Moreover, we will also expand our research of the TET genes into other tumors. We have already had knockout mouse models for all the three individual Tet genes.

MicroRNA Research
MicroRNAs are a group of small RNA molecules important for post-transcriptional regulation. The Chen laboratory has been conducting microRNA research since 2006. The lab has made substantial contributions to advance our understanding of the functions and molecular mechanisms of microRNA regulation in leukemia, especially AML. Our work has provided new insight into the biology of AML by demonstrating that microRNAs can not only serve as biomarkers for the diagnosis and prognosis in AML, but also play critical oncogenic or tumor-suppressor roles in the initiation, progression and drug resistance of AML (see our publication examples: PNAS 2007; PNAS 2008; Cancer Research 2009; PNAS 2010; Blood 2012; Nature Communications 2012; Cancer Cell 2012; PNAS 2012; PNAS 2013; Blood 2015; Cancer Letter 2016; Nature Communications 2016). The new exploration into microRNAs is focusing on their therapeutic implications and their connections to DNA/RNA epigenetics.

Cancer Omics
The Chen laboratory has extensive experiences in conducting large-scale, genome-wide expression profiling assays to identify protein-coding genes and non-coding genes (e.g., microRNAs) that are abnormally expressed in leukemia  (see our publication examples: PNAS 2007; PNAS 2008; Cancer Research 2009; Blood 2012; Nature Communications 2012; Cancer Cell 2012; PNAS 2012; J Clin Oncol 2013; PNAS 2013; Blood 2015; Cancer Letter 2016; Cancer Research 2016a; Nature Communications 2016). We have identified a set of leukemia-associated microRNAs and protein-coding genes that play important oncogenic or tumor-suppressor roles in leukemia and thus they can serve as biomarkers for leukemia diagnosis and/or prognosis, or targets for leukemia therapy. We will continue to conduct cancer omics research by integrating RNA-seq, ChIP-seq, 5mC/5hmC-seq, m6A-seq, and proteomics data. We aim to better understand the complicated signaling networks in cancers, and to identify advanced biomarkers and therapeutic targets for clinical application.

Translational Research
The ultimate goal of our research is to develop novel therapeutic strategies to treat cancers with high efficacy and minimal side effects, based on better understanding of the genetic and epigenetic mechanisms underlying cancer initiation, progression, and maintenance as well as drug response/resistance. The Chen laboratory has established several novel prognostic models for better outcome prediction and risk stratification of leukemia patients (see Blood 2012; J Clin Oncol 2013), and has developed several effective novel targeted therapy strategies to treat leukemia (Nature Communications 2016; Cancer Research 2016b). Our translational research aims at launching clinical trials to improve cancer therapy in the near future.

Other Research Topics
The Chen lab also has a strong interest in conducting stem cell/cancer stem cell research, cancer immunology, reprogramming of somatic/hematopoietic cells using microRNAs or small-molecule compounds to generate hematopoietic stem cells for bone marrow transplantation, circadian research, and genome editing-based research, etc.