prof. Panos Ntziachristos (PhD)
Full Professor - Lab for Leukemia Therapy Resistance (Center for Medical Genetics & Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences), Ghent University
Acute leukemia, both of myeloid and lymphoid origin, is a very prevalent cancer in kids and adults. Unfortunately, frontline radiation and chemotherapy causes lasting cognitive problems and can also lead to secondary cancers. Additionally, about one-fourth of children and 50% of adults with acute leukemia develop resistance to therapy or relapse post therapy.
Mechanisms of resistance are poorly understood and current research on oncogenesis (the development of cancer) mainly focuses on alterations (“mutations”) of gene units in leukemia. Recent studies show that aberrant patterns of transcripts - pieces of RNA stitched together via a process called “splicing” - are critical factors in oncogenesis.
We have discovered that proteins controlling transcript stitching are aberrantly stabilized and have identified that this leads to abnormal splicing patterns. This phenomenon creates generations of transcripts not found in normal cells, ultimately leading to resistance to therapy. We aim to define mechanisms of therapy resistance related to transcript stitching and protein stability in high-risk leukemia by directly comparing therapy-responsive or resistant leukemia cases to each other and to healthy samples. We will also suggest therapeutic platforms for patients using relevant models of disease that can translate to clinical trials. This approach is at the heart of personalized medicine, as it takes into consideration protein levels for candidate proteins to target drug resistance.
I am a professor at the Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University. My research program comprises related inquiries regarding post-translational and epigenetic aspects of leukemia biology and how they control drug resistance. More recently, I have focused on deubiquitination and the effect of the process on large biochemical complexes, such as the splicing machinery, seeking answers to the following questions:
- What are the post-translational modifications that control the function and protein levels of large complexes, such as the splicing machinery, and how they communicate with each other?
- What are the enzymes that control this posttranslational regulation?
- What is the impact of this post-translational splicing regulation on splicing function and drug resistance in malignancy? It is known that pediatric tumors present with a lower mutation burden than adult cancers, including mutations affecting the splicing machinery. In light of this information I am also asking
- what is the contribution of splicing mutations vs. increased protein levels of the splicing machinery on aberrant splicing in cancer and how do these processes coordinate to promote abnormal splicing in cancer?
My past and current research has shown, for the first time in leukemia, that oncogenes antagonize heterochromatin marks, and enzymes controlling these marks may play pivotal roles in cancer development. Specifically, I demonstrated that the polycomb repressive complex 2 is a tumor suppressor, and JMJD3 demethylase is a pro-oncogenic factor in leukemia (Ntziachristos et al., Nature Medicine 2012 and Nature 2014). In the Nature story, I also demonstrated that UTX is a tumor suppressor in leukemia. I was a member of the team that identified that long non-coding RNAs control expression of oncogenic targets through genomic contacts, using chromatin conformation capture technologies (Trimarchi et al., Cell, 2014) and I have led studies to characterize oncogenic three-dimensional chromatin domains (Kloetgen*, Thandapani*, Ntziachristos* et al., Nature Genetics, 2020, *equal contribution) and the oncogenic CTCF binding in blood and solid tumors (Fang, …Ntziachristos& and Zang&, Genome Biology, 2020, &co-senior/co-corresponding author). I have also helped bioinformatics teams with analyses and development of new approaches for the analysis of chromatin conformation data (Lazaris C., BMC Genomics, 2017 and Gong et al., Nature Communications, 2018).
A major line of research in my independent laboratory is related to active deubiquitination in leukemia. Ubiquitination, the addition of ubiquitin moieties to proteins, is a critical post-translational modification that controls stability and levels, as well as signaling potential or activity of proteins, and can go awry in cancer and other diseases. Nevertheless, the process of deubiquitination is not well characterized in leukemia. Using the ubiquitin-specific protease 7 (USP7) as a proof-of-principle molecule, we have shown that deubiquitinases (DUBs) can be members of oncogenic transcriptional complexes. We also shown that inhibition of deubiquitination blocked leukemia cell growth in vitro and in vivo (Jin et al., Clinical Cancer Research, 2019). Our current studies show that specific deubiquitinases are upregulated in aggressive high-risk cases of leukemia and suggest that expression of deubiquitinases might be a prognostic marker in leukemia and deubiquitinase inhibition could be a therapeutic tool against aggressive leukemia. Important aspects of tumor biology affected by deubiquitination include oncogenes, such as NOTCH1, and aberrant splicing. We investigate these aspects in our group with a focus on the serine/arginine-rich splicing factors (such as SRSF6) and how they are regulated by USP7 (Zhou et al., Cancer Discovery, 2020).
Similar to USP7, we have identified other deubiquitinases with critical roles in relapsed and refractory T cell leukemia. My group has ongoing projects focusing on how deubiquitination controls therapy resistance leading to refractory or relapsed disease.
- Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation. Genome Biology, 2020, 32933554
- Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia. Cancer Discovery, 2020, 32444465
- Dynamic 3D chromosomal landscapes in acute leukemia, Nature Genetics, 2020, 32203470
- USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in T cell leukemia. Clinical Cancer Research, 2019, 30224337
- Simultaneous deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nature Genetics, 2016, 27776115
- Contrasting roles for histone 3 lysine 27 demethylases in acute lymphoblastic leukemia. Nature, 2014, 25132549
- Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell, 2014, 25083870
- Genetic Inactivation of the polycomb repressive complex 2 in T-cell acute lymphoblastic leukemia. Nature Medicine, 2012, 22237151