Showing papers by "Eirini P. Papapetrou published in 2019"
Agency for Science, Technology and Research1, National University of Singapore2, Cornell University3, Memorial Sloan Kettering Cancer Center4, European Institute of Oncology5, Icahn School of Medicine at Mount Sinai6, GlaxoSmithKline7, Structural Genomics Consortium8, Erasmus University Medical Center9, Ontario Institute for Cancer Research10
TL;DR: It is identified that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I proteinArginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts.
165 citations
TL;DR: Induced pluripotent stem cells (iPSC) are derived from somatic cells through a reprogramming process, which converts them to a pluripototent state, akin to that of embryonic stem cells.
Abstract: Induced pluripotent stem cells (iPSCs) are derived from somatic cells through a reprogramming process, which converts them to a pluripotent state, akin to that of embryonic stem cells. Over the past decade, iPSC models have found increasing applications in the study of human diseases, with blood disorders featuring prominently. Here, we discuss methodological aspects pertaining to iPSC generation, hematopoietic differentiation and gene editing, and provide an overview of uses of iPSCs in modeling the cell and gene therapy of inherited genetic blood disorders, as well as their more recent use as models of myeloid malignancies. We also discuss the strengths and limitations of iPSCs compared to model organisms and other cellular systems commonly used in hematology research.
29 citations
TL;DR: Comparisons of the malignant phenotypes and molecular signatures of primary leukemic cells, derived iPSCs, and their hematopoietic progeny stress the importance of the cell-of-origin in oncogenesis and enable investigation of the interplay between cell identity and the cancer genome.
17 citations
TL;DR: The results identified a potential targetable vulnerability to improve hematopoiesis in an MDS-predisposition syndrome, and highlight the importance of the germline context of somatic alterations to inform precision medicine approaches to therapy.
Abstract: Monosomy 7 or deletion of 7q (del(7q)) are common clonal cytogenetic abnormalities associated with high grade myelodysplastic syndrome (MDS) arising in inherited and acquired bone marrow failure. Current non-transplant approaches to treat marrow failure may be complicated by stimulation of clonal outgrowth. To study the biological consequences of del(7q) within the context of a failing marrow, we generated induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS), a bone marrow failure disorder with MDS predisposition, and genomically engineered a 7q deletion. The TGFβ pathway was the top differentially regulated pathway in transcriptomic analysis of SDS versus SDSdel(7q) iPSCs. SMAD2 phosphorylation was increased in SDS relative to wild type cells consistent with hyperactivation of the TGFbeta pathway in SDS. Phospho-SMAD2 levels were reduced following 7q deletion in SDS cells and increased upon restoration of 7q diploidy. Inhibition of the TGFbeta pathway rescued hematopoiesis in SDS-iPSCs and in bone marrow hematopoietic cells from SDS patients while it had no impact on the SDSdel(7q) cells. These results identified a potential targetable vulnerability to improve hematopoiesis in an MDS-predisposition syndrome, and highlight the importance of the germline context of somatic alterations to inform precision medicine approaches to therapy.
12 citations
TL;DR: Practical aspects of iPSC modeling of malignant diseases, review recent studies, and discuss the new opportunities that iPSCs offer, as well as their current limitations and prospects for future development are discussed.
Abstract: The reprogramming of human somatic cells into induced pluripotent stem cells (iPSCs) a little over a decade ago raised exciting prospects to transform the study and potentially also the therapy of human diseases. iPSC models have now been created for a multitude of hematologic diseases, including malignancies. Here we discuss practical aspects of iPSC modeling of malignant diseases, review recent studies, and discuss the new opportunities that iPSC models offer, as well as their current limitations and prospects for future development.
8 citations
TL;DR: The effects of the common SF3B1 K700E mutation on R-loop formation and DNA damage response in MDS and leukemia cells is investigated and increased Chk1 phosphorylation at Ser345, a hallmark of activation of the ATR pathway, is observed in SF3b1 mutant K562 cells.
4 citations