- ASSOCIATE PROFESSOR Oncological Sciences
- ASSOCIATE PROFESSOR Medicine, Hematology and Medical Oncology
MD, University of Patras, Greece
PhD, University of Patras, Greece
Postdoctoral, Memorial Sloan-Kettering Cancer Center
- Papapetrou lab website: http://katahdin.mssm.edu/papapetrou_lab
Eirini Papapetrou earned her MD and PhD from th University of Patras in Greece. As a postdoctoral fellow in Memorial Sloan-Kettering Cancer Center she developed some of the first disease and cell and gene therapy models utilizing human induced pluripotent stem cells. In 2012 she joined the faculty of the University of Washington and was subsequently recruited to Mount Sinai in 2014.
American Society for Clinical Investigation Young Physician-Scientist Award
American Society for Clinical Investigation (ASCI)
Aplastic Anemia & MDS IF Research Grant Award
Aplastic Anemia & MDS International Foundation
2013 - 2014
John H. Tietze Stem Cell Scientist Award
2013 - 2014
UW Royalty Research Fund Award
University of Washington
Ellison Medical Foundation New Scholar in Aging Award
Ellison Medical Foundation
Damon Runyon-Rachleff Innovation Award
Damon Runyon Cancer Research Foundation
American Society of Hematology (ASH) Junior Faculty Scholar Award
American Society of Hematology (ASH)
Sidney Kimmel Foundation Scholar Award
Sidney Kimmel Foundation for Cancer Research
K99/R00 Pathway to Independence Award
A. Research overview:
Cellular alchemy meets genome engineering
We use human pluripotent stem cells to understand the mechanisms of malignant and non-malignant genetic blood diseases and to develop new therapies. We are harnessing somatic cell reprogramming and genetic engineering technologies to develop new models of normal and abnormal hematopoiesis. By capturing and introducing disease-associated genetic mutations and large chromosomal deletions in patient-derived induced pluripotent stem cells (iPSCs) we study their phenotypic and functional consequences, attempt to reconstruct the genetic history of leukemia progression and seek to identify new therapeutic targets through genetic screens.
Functional genetics with human pluripotent stem cells
Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by ineffective hematopoiesis - manifested as peripheral blood cytopenia and dysplastic bone marrow (BM) - and a propensity for progression to BM failure or acute myeloid leukemia (AML) with poor prognosis. Although relatively common diseases, their pathogenesis is poorly understood.
We have recently established iPSC models of MDS that offer exciting new possibilities for the study of the molecular pathogenesis of MDS and the investigation of its genetics, clonal evolution and progression to leukemia and can provide a powerful platform for phenotype-based genetic and chemical screens to identify new therapeutic targets. We have also developed new strategies, combining AAV-mediated gene targeting with modified Cre-lox technology, as well as with the Cas9-CRISPR system, to engineer targeted chromosomal deletions in human iPSCs. These offer new opportunities to interrogate the functional consequences of large copy number variants associated with human cancer.
Discovery of haploinsufficient genes on chromosome 7q. Loss of one copy of part of Chr7q [del(7q)] is a recurrent karyotypic abnormality intimately linked to the pathogenesis of MDS. Despite a decades-long quest, the critical gene(s) residing on chr7q remain elusive. We found that the hematopoietic phenotypes of our MDS-iPSC model are rescued by compensation of Chr7q dosage through spontaneous duplication and recapitulated by engineered deletions spanning a ~20 Mb Chr7q region. These results support a model of gene haploinsufficiency underlying the pathogenesis of MDS and define a critical chromosome 7q region. To further narrow down the critical chr7q region we developed innovative strategies, combining AAV-mediated gene targeting with Cre-lox and Cas9-CRISPR technologies, in order to derive panels of iPSC clones harboring deletions of variable lengths along chr7q, that will allow us to functionally map the MDS phenotypes to a yet smaller region of only few Mb. To functionally identify critical genes on chr7q we have compiled a list of 62 candidate haploinsufficient genes (whose expression is reduced by at least 1.5-fold in our isogenic pairs of del(7q)-iPSCs), constructed a barcoded lentiviral ORF library and we are performing screens for genes that rescue hematopoiesis in our del(7q)-MDS-iPSCs.
Clonal evolution of MDS/AML. Clonal heterogeneity represents a clinically very important feature of the cancer genome, as it forms the basis for the wide variations in tumor behavior and responsiveness to therapy and serves as a reservoir of genetic diversity from which resistant clones may arise. Recent whole genome sequencing studies (WGS) showed that the BM of MDS patients is often oligoclonal, i.e. contains multiple cell populations with distinct patterns of acquired mutations, consistent with a model whereby MDS is initiated in a cell (the “founding clone”) that subsequently acquires additional mutations to form daughter subclones. However, no direct evidence for the existence of subclones exists (they are indirectly inferred by the variant allele frequencies, VAFs, in the cell populations) and subclones that comprise less than 20% of the population are inaccessible with current WGS techniques. Furthermore, it is not known whether specific mutations occur typically at specific stages during disease progression and the biological significance of most of them remains poorly understood. Cellular reprogramming is an inherently clonal process and thus enables the “capture” of single cell genomes. We use whole exome sequencing (WES) in paired MDS BM cell samples and skin or BM fibroblasts (as matched normal tissue) and “deep reprogramming” to capture all possible subclones, in order to reconstruct the genetic ancestry and attempt to draw phenotype-genotype connections.
A universal safe harbor site in the human genome. Many research and gene therapy applications require the addition of genes into human cells in a manner that ensures robust and reliable expression without the dysregulation of endogenous genes which can lead to oncogenesis, as seen in gene therapy clinical trials. With the advent of gene targeting technologies, the development of efficient and universal approaches to the transgenesis of human cells is becoming a realistic prospect. However, the development of technologies for targeted gene integration has not been paralleled by the identification of appropriate target sites in the human genome. We have proposed a framework based on bioinformatics and functional studies for the selection of genomic safe harbors (GSHs), sites that are able to accommodate predictable expression of newly integrated DNA without adverse effect on the host cell or organism. We have designed lentiviral vectors amenable to recombinase-mediated cassette exchange (RMCE) to perform a genome-wide screen to identify and test candidate universal safe harbors.
Conditional suicide gene strategies for protection from teratoma formation in pluripotent stem cell-based therapies. Human pluripotent stem cells offer great promise for cell therapies. However, a major concern - inherent to their pluripotent nature - is the risk of teratoma formation. To confer protection against teratoma-initiating pluripotent cells potentially contaminating a differentiated cell graft, we have engineered an HSV-tk suicide gene under post-transcriptional regulation by let7 miRNAs -a miRNA family widely expressed in all differentiated cell types but not in undifferentiated stem cells- so that undifferentiated iPSCs expressing tk-let7 are sensitive to killing by ganciclovir, whereas their differentiated progeny are protected. We are testing the efficacy of this approach in teratoma formation assays and after engraftment of iPSC-derived cells in mouse models.
Hammachi F, Morrison GM, Sharov AA, Livigni A, Narayan S, Papapetrou EP, O'Malley J, Kaji K, Ko MS, Ptashne M, Brickman JM. Transcriptional activation by Oct4 is sufficient for the maintenance and induction of pluripotency. Cell reports 2012 Feb; 1(2).
Papapetrou EP. FA iPS: correction or reprogramming first?. Blood 2012 Jun; 119(23).
Sadelain M, Papapetrou EP, Bushman FD. Safe harbours for the integration of new DNA in the human genome. Nature reviews. Cancer 2012 Jan; 12(1).
Papapetrou EP, Sadelain M. Derivation of genetically modified human pluripotent stem cells with integrated transgenes at unique mapped genomic sites. Nature protocols 2011 Sep; 6(9).
Papapetrou EP, Sadelain M. Generation of transgene-free human induced pluripotent stem cells with an excisable single polycistronic vector. Nature protocols 2011 Sep; 6(9).
Kim H, Lee G, Ganat Y, Papapetrou EP, Lipchina I, Socci ND, Sadelain M, Studer L. miR-371-3 expression predicts neural differentiation propensity in human pluripotent stem cells. Cell stem cell 2011 Jun; 8(6).
Brady T, Roth SL, Malani N, Wang GP, Berry CC, Leboulch P, Hacein-Bey-Abina S, Cavazzana-Calvo M, Papapetrou EP, Sadelain M, Savilahti H, Bushman FD. A method to sequence and quantify DNA integration for monitoring outcome in gene therapy. Nucleic acids research 2011 Jun; 39(11).
Müller FJ, Schuldt BM, Williams R, Mason D, Altun G, Papapetrou EP, Danner S, Goldmann JE, Herbst A, Schmidt NO, Aldenhoff JB, Laurent LC, Loring JF. A bioinformatic assay for pluripotency in human cells. Nature methods 2011 Apr; 8(4).
Papapetrou EP, Lee G, Malani N, Setty M, Riviere I, Tirunagari LM, Kadota K, Roth SL, Giardina P, Viale A, Leslie C, Bushman FD, Studer L, Sadelain M. Genomic safe harbors permit high β-globin transgene expression in thalassemia induced pluripotent stem cells. Nature biotechnology 2011 Jan; 29(1).
Papapetrou EP, Sadelain M. Reconstructing blood from induced pluripotent stem cells. F1000 medicine reports 2010; 2.
Yang JS, Maurin T, Robine N, Rasmussen KD, Jeffrey KL, Chandwani R, Papapetrou EP, Sadelain M, O'Carroll D, Lai EC. Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proceedings of the National Academy of Sciences of the United States of America 2010 Aug; 107(34).
Papapetrou EP, Korkola JE, Sadelain M. A genetic strategy for single and combinatorial analysis of miRNA function in mammalian hematopoietic stem cells. Stem cells (Dayton, Ohio) 2010 Feb; 28(2).
Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, Ganat YM, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 2009 Sep; 461(7262).
Papapetrou EP, Tomishima MJ, Chambers SM, Mica Y, Reed E, Menon J, Tabar V, Mo Q, Studer L, Sadelain M. Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation. Proceedings of the National Academy of Sciences of the United States of America 2009 Aug; 106(31).
Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature biotechnology 2009 Mar; 27(3).
Papapetrou EP, Kovalovsky D, Beloeil L, Sant'angelo D, Sadelain M. Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras. The Journal of clinical investigation 2009 Jan; 119(1).
Papapetrou EP, Zoumbos NC, Athanassiadou A. Genetic modification of hematopoietic stem cells with nonviral systems: past progress and future prospects. Gene therapy 2005 Oct; 12 Suppl 1.
Papapetrou EP, Ziros PG, Micheva ID, Zoumbos NC, Athanassiadou A. Gene transfer into human hematopoietic progenitor cells with an episomal vector carrying an S/MAR element. Gene therapy 2006 Jan; 13(1).
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Dr. Papapetrou did not report having any of the following types of financial relationships with industry during 2013 and/or 2014: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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