Molecular Oncology and Biomarkers


Jan van Riggelen, PhD

Jan van Riggelen, PhD

Molecular Oncology and Biomarkers Program
Assistant Professor of Biochemistry and Molecular Biology
Associate Professor, Graduate Studies

 



Georgia Cancer Center
1410 Laney Walker Blvd., CN-2175
Office: 706-721-0856
Lab: 706-721-0823
Email: jvanriggelen@augusta.edu

Research Summary

Research in my laboratory focuses on how the MYC oncogene regulates tumor maintenance, regression and relapse through epigenetic mechanisms using mouse models, human tumor cell lines and clinical specimens. Our goal is the discovery and validation of novel targets for therapeutic strategies.

Research Interests

MYC and genome-wide regulation of chromatin structure

The MYC oncogene is an important driver of neoplastic transformation and is implicated in the pathogenesis of a wide variety of human cancers including hematopoietic malignancies. Deregulated expression of MYC is a frequent abnormality in many aggressive B- and T-cell lymphomas including Burkitt’s lymphoma and T-cell acute lymphoblastic leukemia (T-ALL). Intriguingly, the genetic inactivation of MYC is a highly effective strategy that can cause tumor regression by exploiting the phenomenon of oncogene addiction.

We are currently working on identifying transcriptional targets and co-regulatory factors of MYC that are essential for tumor maintenance and can be utilized as therapeutic targets. 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 activity and dynamics of genome-wide DNA methylation through MYC.

DNMT3B overexpression contributes to MYC-driven tumor maintenance in T-ALL and Burkitt’s lymphoma.

In T- and B-cell malignancies, the MYC oncogene directly controls genome-wide DNA methylation through a novel mechanism, by deregulating transcription of DNMT3B.

We found that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt’s lymphoma the MYC oncogene causes overexpression of DNA methyltransferase (DNMT) 1 and 3B, which contribute to tumor maintenance. By utilizing a tetracycline-regulated MYC transgene in a mouse T-ALL (EµSRα-tTA;tet-o-MYC) and human Burkitt’s lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC inactivation. Chromatin immunoprecipitation indicated that MYC binds to the DNMT1 and DNMT3B promoters, implicating a direct transcriptional regulation. Hence, shRNA-mediated knockdown of endogenous MYC in human T-ALL and Burkitt’s lymphoma cell lines downregulated DNMT3B expression. Knock-down and pharmacologic inhibition of DNMT3B in T-ALL reduced cell proliferation associated with genome-wide changes in DNA methylation, indicating a tumor promoter function during tumor maintenance. We provide novel 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. Our finding that a coordinated interplay between the components of the DNA methylating machinery contributes to MYC-driven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.

Selected Publications

  1. 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. In press
  1. Poole CP and van Riggelen J. (2017) MYC – Master Regulator of the Cancer Epigenome and Transcriptome. Genes (Basel). 8(5).
  1. 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.
  1. Wu AR, Kawahara TL, Rapicavoli NA, van Riggelen J, Shroff EH, Xu L, Felsher DW, Chang HY, Quake SR. (2012) High throughput automated chromatin immunoprecipitation as a platform for drug screening and antibody validation. Lab Chip. 12: 2190-8.
  1. Choi PS*, van Riggelen J*, Gentles AJ, Bachireddy P, Rakhra K, Adam SJ, Plevritis SK and Felsher DW. (2012) Persistent addiction to MYC expression in reoccurring lymphomas. Proc Natl Acad Sci U S A. 108: 17432-7.
  1. Müller J, Samans B, van Riggelen J, Fagà G, Peh R, Wei CL, Müller H, Amati B, Felsher DW and Eilers M. (2010) TGF beta-dependent gene expression shows that senescence correlates with abortive differentiation along several lineages in Myc-induced lymphomas. Cell Cycle. 9, 4622-4626.
  1. van Riggelen J, Yetil A, Felsher DW. (2010) MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 10: 301-309.
  1. van Riggelen J, and Felsher DW. (2010) Myc and a Cdk2 Senescence Switch. Nat Cell Biol. 12: 7-9.
  1. van Riggelen J*, Müller J*, Otto T*, Beuger V, Samans B, Yetil A, Choi PS, Kosan C, Möröy T, Felsher DW, Eilers M. (2010) The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance. Genes Dev. 24: 1281-1294
  1. Wu CW, van Riggelen J, Yetil A, Bachireddy P, Fan A, Felsher DW. (2007) Cellular Senescence is an Important Mechanism of Tumor Regression upon MYC-Inactivation. Proc Natl Acad Sci U S A. 104: 13028-33.

Awards & Funding

  • Augusta University – BMB Translational Research Pilot Award 2017 – 2018
  • American Cancer Society – Institutional Research Grant (#IRG14-193-01) 2016 – 2017
  • Lymphoma Research Foundation – Postdoctoral Fellowship 2006 – 2008

Research Team

photo of Candace J. Poole
Candace J. Poole

Graduate Student
photo of Atul Lodh 
Atul Lodh 

Research Assistant