Jan van Riggelen's Lab Page


van Riggelen Laboratory:
We study the epigenetic aspect of self-renewal and cellular differentiation in cancer using cell and molecular biology approaches. We are interested in how the functional properties of transcription factors that determine cell fate are dependent on epigenetic mechanisms.

Research Focus:
Cancer epigenetics - MYC oncogene - leukemia and lymphoma - DNA methylation

Lab Members:

 vanriggelen

Jan van Riggelen, PhD – Assistant Professor
Biochemistry and Molecular Biology Department
Member Georgia Cancer Center at Augusta University
Member College of Graduate Studies at Augusta University
Email: jvanriggelen at augusta.edu

Dr. van Riggelen received his PhD from the Ruprecht-Karls University Heidelberg, Germany for his work at the German Cancer Research Center (DKFZ) with Frank Roesl, PhD and Harald zur Hausen, MD (Nobel Laureate 2008). Before he came to Augusta University he trained as postdoctoral fellow at Stanford University with Dean W. Felsher, MD, PhD.

 poole

Candace J. Poole – Graduate Research Assistant
Biochemistry and Molecular Biology Department
Member Biomedical Student Association at Augusta University
Member Graduate School Student Council at Augusta University
Member Georgia Bio: Emerging Leaders Network Liaison for Augusta University.
Email: capoole at augusta.edu

Candace Poole received her B.S. in Cellular and Molecular Biology from Armstrong State University in Savannah, GA. She is now pursuing her PhD in Biochemistry and Cancer Biology. Her interests include cancer biology, epigenetics, and pharmacology. She is planning to pursue a career in the pharmaceutical industry.

 lodh

Atul Lodh – Research Assistant

Email: alodh at augusta.edu

Atul Lodh received his B.S. in Genetics and Psychology with a Neuroscience Emphasis from the University of Georgia in Athens, GA. He is planning on attending medical school to pursue a career as physician scientist. 

 myc

MYC – Enigmatic oncogene

Was first discovered as myelocytomatosis viral oncogene, later also found in Burkitt lymphoma patients and many other human cancer types. Belongs to family of transcription factors contain a bHLH (basic helix-loop-helix) structural and LZ (leucine zipper) motives.

The MYC Oncogene – Master Regulator of the Cancer Epigenome and Transcriptome

Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. myc2

 However, MYC’s influence on many of these target genes is rather modest and there is little overlap between MYC regulated genes in different cell types, leaving many mechanistic questions unanswered. Recent advances in the field challenge the dogma further, revealing a role for MYC that extends beyond the traditional concept of a sequence-specific transcription factor (reviewed in Poole and van Riggelen, Genes 2017).

Cellular senescence as key mechanism for tumor regression upon oncogene inactivation

One of the key steps during tumorigenesis is ability to bypass the mechanisms that limit the lifespan of normal cells and enable tumor cells to proliferate indefinitely. In order to gain immortality cells have to overcome an irreversible growth-arrest termed cellular senescence, which functions as fail-safe mechanism for uncontrolled proliferation and barrier for tumorigenesis. Hence, the mechanisms eliciting oncogene-induced senescence were believed to be permanently deactivated in cancer cells. However, we showed in a variety of different tumor types, that the fail-safe mechanism of cellular senescence can be reactivated by inactivating a single oncogene such as MYC (Wu et al., PNAS 2008).

In fact, cellular senescence is the key mechanism to induce tumor regression upon inactivation of the MYC oncogene. We found that in T-cell acute lymphoblastic leukemia (T-ALL) the transforming growth factor (TGF)-beta pathway is constitutively active and forms an autocrine feedback loop that is required to induce cellular senescence and sustained tumor regression upon MYC inactivation (van Riggelen et al., Genes & Dev 2010).

The epigenetic aspect of self-renewal and cellular differentiation in cancer

Currently, we use the MYC/MIZ1 network and SMAD/TGF-beta signaling pathway in hematopoietic malignancies as a model system to study how dynamics in the epigenetic landscape affect the properties of key transcriptional regulators to drive proliferation vs. cellular senescence. Conversely, we are interested in how these transcription factors themselves determine the cellular phenotype by altering chromatin structure on a genome-wide level. The main focus is on spatial and temporal control of DNA methyltransferase (DNMT) activity and dynamics of genome-wide DNA methylation through MYC.

MYC oncogene directly controls genome-wide DNA methylation

We recently reported that in T- and B-cell malignancies the MYC oncogene directly controls genome-wide DNA methylation through a novel mechanism deregulating transcription of DNMT3B (Poole et al., Oncotarget 2017).

We showed that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt’s lymphoma MYC causes overexpression of DNMT1 and DNMT3B, which contributes to tumor maintenance. This provides the first evidence that MYC directly deregulates the expression of both de novo and maintenance DNMTs, showing that MYC controls DNA methylation in a genome-wide fashion. Furthermore, it shows that a coordinated interplay between the components of the DNA methylating machinery contributes to MYC-driven tumor maintenance, highlighting the potential of specific DNMTs for targeted anti-cancer therapies.

 myc3

 Key References:

Poole CP*, Zheng W*, Lodh A, Yevtodiyenko A, Liefwalker D, Li H, Felsher DW and van Riggelen J. (2017) DNMT3B overexpression contributes to MYC-driven tumor maintenance in T-ALL and Burkitt’s lymphoma. Oncotarget. 8: 76898-76920. [PubMed]

Poole CP and van Riggelen J. (2017) MYC – Master Regulator of the Cancer Epigenome and Transcriptome. Genes (Basel). 8(5). [PubMed]

Yetil A, Anchang B, Gouw A, Adam SJ, Zabuawala T, Parameswaran R, van Riggelen J, Plevritis S and Felsher DW. (2015) p19ARF is a critical mediator of cellular senescence and the innate immune response associated with MYC suppression in acute leukemia. Oncotarget. 6: 3563-3577. [PubMed]

Wu AR, Kawahara TL, Rapicavoli NA, van Riggelen J, Shroff EH, Xu L, Felsher DW, Chang HY, Quake SR. High throughput automated chromatin immunoprecipitation as a platform for drug screening and antibody validation. Lab Chip. 2012 Jun 21;12(12):2190-8. [PubMed]

Choi PS, van Riggelen J, Gentles AJ, Bachireddy P, Rakhra K, Adam SJ, Plevritis SK, Felsher DW. Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction. Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17432-7. [PubMed]

Müller J, Samans B, van Riggelen J, Fagà G, Peh K N R, Wei CL, Müller H, Amati B, Felsher D, Eilers M. TGFβ-dependent gene expression shows that senescence correlates with abortive differentiation along several lineages in Myc-induced lymphomas. Cell Cycle. 2010 Dec 1;9(23):4622-6. [PubMed]

van Riggelen J, Müller J, Otto T, Beuger V, Yetil A, Choi PS, Kosan C, Möröy T, Felsher DW, Eilers M. The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance. Genes Dev. 2010 Jun 15;24(12):1281-94. [PubMed]

van Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010 Apr;10(4):301-9. Review. [PubMed]

van Riggelen J, Felsher DW. Myc and a Cdk2 senescence switch. Nat Cell Biol. 2010 Jan;12(1):7-9. Review. [PubMed]

Wu CH, van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13028-33. [PubMed]

Giuriato S, Ryeom S, Fan AC, Bachireddy P, Lynch RC, Rioth MJ, van Riggelen J, Kopelman AM, Passegué E, Tang F, Folkman J, Felsher DW. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16266-71. [PubMed]