Experimental hematology, Myeloproliferative Neoplasms, Lab Dr. med. A. Theocharides

Myeloproliferative neoplasms (MPN) are pre-leukemic hematopoietic stem cell disorders characterized by increased proliferation of one or more hematopoietic cell lineages. The incidence of MPN is highest in the aging population and MPN prevalence will significantly increase in the next decades. Although recent advances in diagnosis and subsequent therapies led to improved MPN patient survival, most patients die from cardiovascular events or from transformation to acute leukemia.
The goal of our research is to gain understanding of the pathogenesis of MPN and to translate this knowledge into the development of novel therapeutic approaches. As murine models only partially reflect the complexity of human disease, a substantial part of the experiments are performed with primary patient cells in vitro and in vivo in patient-derived xenograft models. For this we have access to multiple next-generation immunodeficient mice that the group of M.G. Manz has generated within a consortium. I am also an attendig physician of the outpatient clinic for patients with MPN in the division of hematology at the University Hospital Zurich. The research platform and the strong interactions with the division of hematology constitute an ideal and attractive infrastructure to assess efficacy of therapeutic compounds and collaborate with the pharmaceutical industry to further translate evidence established in our laboratory to clinical trials.  

Projects

​​Veronika Lysenko

Development of a patient-derived xenograft model for myelofibrosis

A growing number of patient-derived xenograft (PDX) mouse models have been developed over the past few decades that allow engraftment of human hematopoietic stem cell (HSC) malignancies in order to study their evolution, as well as disease heterogeneity. However, engraftment is often limited due to potential lack of supportive factors in the bone marrow (BM) microenvironment. This limitation facilitated the development of more advanced mouse strains that express human cytokines and growth factors that are needed for efficient human hematopoietic development in vivo. Myelofibrosis (MF) is a HSC disorder characterized by bone marrow fibrosis that has the potential to transform into acute myeloid leukemia depending on the clonal evolution of MF stem cells (MF SCs). However, the engraftment of MF SCs in PDX models is poor (Wang et al., JCI 2012). We hypothesize that the constitutive expression of human cytokines and growth factors in a PDX model may promote the development of the human MF clone in vivo. Therefore, the aim of my project will be to use next-generation mice in order to develop a pre-clinical MF PDX model and determine whether specific somatic mutations promote human MF engraftment. Moreover, track clonal evolution in vivo and correlate with disease progression in patients. 


 

​Patrick Schürch

The role of Calreticulin mutations in the pathogenesis of MPN

Myeloproliferative neoplasms (MPN) are characterized by frequent somatic mutations in the Januskinase 2 (JAK2) and Calreticulin (CALR). CALR is a highly conserved chaperone that resides in endoplasmic reticulum (ER) that folds N-linked glycoproteins (GP). Recently, our group has shown that MPN patients with homozygous CALR mutations develop a maturation defect in Myeloperoxidase (MPO), a GP normally folded by CALR (Theocharides et al., Blood 2016). Based on these findings, we hypothesize that CALR mutations affect GP maturation and potentially may lead to mutant-specific protein-protein interactions in signaling pathways that further contribute to the pathogenesis of MPN. We are currently in the process of generating human and mouse CALR mutant cell lines using CRISPR/Cas9 technology that will help us investigate the functional implications of CALR mutants on GP. This project is performed in collaboration with the laboratory of Prof. Wollscheid at the ETHZ.

Publications

2016

Theocharides AP, Lundberg P, Lakkaraju AK, Lysenko V, Myburgh R, Aguzzi A, Skoda RC, Manz MG.
Homozygous Calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency.
Blood. 2016 Mar 24. (Epub ahead of print)
Pubmed



Theocharides AP, Rongvaux A, Fritsch K, Flavell RA, Manz MG.
Humanized hemato-lymphoid system mice.
Haematologica. 2016 Jan; 101 (1):5-19.
Pubmed

 

2015

Mager LF, Riether C, Schürch CM, Banz Y, Wasmer MH, Stuber R, Theocharides AP, Li X, Xia Y, Saito H, Nakae S, Baerlocher GM, Manz MG, McCoy KD, Macpherson AJ, Ochsenbein AF, Beutler B, Krebs P.
IL-33 sginaling contributes to the pathogenesis of myeloproliferative neoplasms
J Clin Invest. 205 Jul 1;125(7):2579.91. Epub 2015 May 26.
Pubmed

2014

Theocharides AP, Dobson SM, Laurenti E, Notta F, Voisin V, Cheng PY, Yuan JS, Guidos CJ, Minden MD, Mullighan CG, Torlakovic E, Dick JE.
Dominant-negative Ikaros cooperates with BCR-ABL1 to induce human acute myeloid leukemia in xenografts.
Leukemia. 2014 May 5. (Epub ahead of print)
Pubmed

2012

Theocharides AP, Jin L, Cheng PY, Prasolva TK, Malko AV, Ho JM, Poeppl AG, van Rooijen N, Minden MD, Danska JS, Dick JE, Wang JC.
Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts.
J Exp Med. 2012 Sep 24;209(10):1883-99. Epub 2012 Sep 3.
Pubmed

2009

Medinger M, Skoda R, Gratwohl A, Theocharides A, Buser A, Heim D, Dirnhofer S, Tichelli A, Tzankov A.
Angiogenesis and vascular endothelial growth factor-/receptor expression in myeloproliferative neoplasms: correlation with clinical parameters and JAK2-V617F mutational status.
Br Haematol. 2009 Jul;146(2):150-7. Epub 2009 May 19.
Pubmed

2008

Theocharides A, Passweg JR, Medinger M, Looser R, Li S, Hao-Shen H, Buser AS, Gratwohl A, Tichelli A, Skoda RC.
The allele burden of JAK2 mutations remains stable over several years in patients with myeloproliferative disorders.
Haematologica. 2008 Dec;93(12):1890-3. Epub 2008 Sep 11.
Pubmed

Tzankov A, Sotlar K, Muhlematter D, Theocharides A, Went P, Jotterand M, Horny HP, Dirnhofer S.
Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involving FLT3.
J Clin Pathol. 2008 Aug;61(8):958-61.
Pubmed

Heim D, Passweg J, Gregor M, Buser A, Theocharides A, Arber C, Meyer-Monard S, Halter J, Tichelli A, Gratwohl A.
Patient and product factors affecting platelet transfusion results.
Transfusion. 2008 Apr;48(4):681-7. Epub 2008 Jan 15.
Pubmed

Li S, Kralovics R, De Libero G, Theocharides A, Gisslinger H, Skoda RC.
Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations.
Blood. 2008 Apr 1;111(7):3863-6. Epub 2008 Jan 14.
Pubmed

Blijlevens N, Schwenkglenks M, Bacon P, D'Addio A, Einsele H, Maertens J, Niederwieser D, Rabitsch W, Roosaar A, Ruutu T, Schouten H, Stone R, Vokurka S, Quinn B, McCann S; European Blood and Marrow Transplantation Mucositis Advisory Group.
Prospective oral mucositis audit: oral mucositis in patients receiving high-dose melphalan or BEAM conditioning chemotherapy--European Blood and Marrow Transplantation Mucositis Advisory Group.
J Clin Oncol. 2008 Mar 20;26(9):1519-25. Epub 2008 Feb 11.
Pubmed

Pietra D, Li S, Brisci A, Passamonti F, Rumi E, Theocharides A, Ferrari M, Gisslinger H, Kralovics R, Cremonesi L, Skoda R, Cazzola M.
Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders.
Blood. 2008 Feb 1;111(3):1686-9. Epub 2007 Nov 5.
Pubmed

2007

Recher M, Lang KS, Navarini A, Hunziker L, Lang PA, Fink K, Freigang S, Georgiev P, Hangartner L, Zellweger R, Bergthaler A, Hegazy AN, Eschli B, Theocharides A, Jeker LT, Merkler D, Odermatt B, Hersberger M, Hengartner H, Zinkernagel RM.
Extralymphatic virus sanctuaries as a consequence of potent T-cell activation.
Nat Med. 2007 Nov;13(11):1316-23. Epub 2007 Nov 4.
Pubmed

Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E, Talmant P, Tichelli A, Hermouet S, Skoda RC.
Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation.
Blood 2007 Jul 1; 110(1):375-9. Epub 2007 Mar 15.
Pubmed

2006

Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A, Skoda RC.
Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders.
Blood. 2006 Aug 15;108(4):1377-80. Epub 2006 May 4.
Pubmed

Recher M, Lang KS, Hunziker L, Freigang S, Eschli B, Harris NL, Navarini A, Senn BM, Fink K, Lötscher M, Hangartner L, Zellweger R, Hersberger M, Theocharides A, Hengartner H, Zinkernagel RM.
Deliberate removal of T cell help improves virus-neutralizing antibody production.
Nat Immunol. 2004 Sep;5(9):934-2. Epub 2004 Aug 8.
Pubmed