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Stephen ArnoffTomasz Skorski, MD, PhD, DSc

 

Professor, Microbiology and Immunology

Associate Professor, Fels Institute

Telephone:  215-707-9157

Fax:  215-707-9160

Email: tskorski@temple.edu

 

Department of Microbiology and Immunology

Fels Institute for Cancer Research and Molecular Biology

 

Educational Background:

 

MD, Medical Academy of Warsaw, Poland, 1982

 

PhD, Medical Center for Postgraduate Education, Warsaw, Poland, 1986

 

DSc, Medical Center for Postgraduate Education, Warsaw, Poland, 1990

 

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Research Interests:

 

Reciprocal chromosomal translocations are responsible for the occurrence of fusion genes, whose products cause leukemic transformation. A cohort of these genes encodes fusion tyrosine kinases (FTKs). Despite remarkable advances in investigations of the mechanisms leading to the leukemic transformation of hematopoietic cells by FTKs, our knowledge about the nature of intracellular phenomena triggered by FTKs is rather limited.


My laboratory focuses on identification of the leukemogenic mechanisms activated by BCR-ABL1 oncogenic tyrosine kinase produced by the Philadelphia chromosome, and by other FTKs (TEL-ABL1, TEL-PDGFβR, TEL-JAK2, NPM-ALK, TEL-TRKC, BCR-FGFR). BCR/ABL gene is derived from relocation of the portion of ABL1 gene from chromosome 9 to the portion of BCR gene locus on chromosome 22 [t(9;22)], and is present in most of chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemia (ALL) patients. BCR-ABL1 hybrid genes produce p230, p210 and p185 fusion proteins (the size depends on the breakpoint in BCR locus) exerting constitutive tyrosine kinase activity, transforming hematopoietic cells in vitro, and causing CML- or ALL- like syndromes in mice.


Initially, my research focused on targeting BCR-ABL1 kinase and its downstream effectors such as Ras, Rac, PI3k, Akt, and STAT5 to eliminate leukemia. In the past 15 years my laboratory focused on determination of the role of signaling pathways generating reactive oxygen species (ROS)-induced oxidative stress in CML leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs). We were first to show that CML primary cells, including LSCs, contain elevated levels of ROS and oxidative DNA damage, including numerous DNA double strand breaks (DSBs). In addition, BCR-ABL1 kinase affects DNA repair pathways: it stimulates unfaithful DSB repair pathways and inhibits mismatch repair pathway. Altogether, these effects cause genomic instability represented by accumulation of imatinib-resistant BCR-ABL1 kinase mutants and additional chromosomal aberrations. Genomic instability induces CML relapse and malignant progression. Our goal is to pinpoint signaling pathways responsible for genomic instability and to target them to prevent disease relapse/progression.


In addition, we found that CML cells utilize different mechanism to repair ROS-induced lethal DSBs in comparison to normal counterparts. Therefore, we are trying to induce “synthetic lethality” in CML stem and progenitor cells by targeting DSB repair mechanisms, to which CML cells are “addicted”.


We are also looking for the opportunity to induce “synthetic lethality” in other tumors based on genetic and epigenetic profiling.

 

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PUBMED PUBLICATIONS :


Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

25228518. Toma M, Skorski T, Sliwinski T, Synthetic lethality as a functional tool in basic research and in anticancer therapy. Postepy Hig Med Dosw (Online) 68:(1091-103)2014 Sep 3

25151958. Nieborowska-Skorska M, Flis S, Skorski T, AKT-induced reactive oxygen species generate imatinib-resistant clones emerging from chronic myeloid leukemia progenitor cells. Leukemia :()2014 Aug 25

23836560. Cramer-Morales K, Nieborowska-Skorska M, Scheibner K, Padget M, Irvine DA, Sliwinski T, Haas K, Lee J, Geng H, Roy D, Slupianek A, Rassool FV, Wasik MA, Childers W, Copland M, Müschen M, Civin CI, Skorski T, Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood 122:7(1293-304)2013 Aug 15

23604228. Nieborowska-Skorska M, Hoser G, Hochhaus A, Stoklosa T, Skorski T, Anti-oxidant vitamin E prevents accumulation of imatinib-resistant BCR-ABL1 kinase mutations in CML-CP xenografts in NSG mice. Leukemia 27:11(2253-4)2013 Nov

23543457. Bolton-Gillespie E, Schemionek M, Klein HU, Flis S, Hoser G, Lange T, Nieborowska-Skorska M, Maier J, Kerstiens L, Koptyra M, Müller MC, Modi H, Stoklosa T, Seferynska I, Bhatia R, Holyoake TL, Koschmieder S, Skorski T, Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells. Blood 121:20(4175-83)2013 May 16

23047475. Slupianek A, Falinski R, Znojek P, Stoklosa T, Flis S, Doneddu V, Pytel D, Synowiec E, Blasiak J, Bellacosa A, Skorski T, BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability. Leukemia 27:3(629-34)2013 Mar

22616753. Flis K, Irvine D, Copland M, Bhatia R, Skorski T, Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation. Leuk Lymphoma 53:12(2474-8)2012 Dec

22411871. Nieborowska-Skorska M, Kopinski PK, Ray R, Hoser G, Ngaba D, Flis S, Cramer K, Reddy MM, Koptyra M, Penserga T, Glodkowska-Mrowka E, Bolton E, Holyoake TL, Eaves CJ, Cerny-Reiterer S, Valent P, Hochhaus A, Hughes TP, van der Kuip H, Sattler M, Wiktor-Jedrzejczak W, Richardson C, Dorrance A, Stoklosa T, Williams DA, Skorski T, Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors. Blood 119:18(4253-63)2012 May 3

22328017. Skorski T, Genetic mechanisms of chronic myeloid leukemia blastic transformation. Curr Hematol Malig Rep 7:2(87-93)2012 Jun

22118668. Skorski T, BCR-ABL1 kinase: hunting an elusive target with new weapons. Chem Biol 18:11(1352-3)2011 Nov 23

22036635. Falinski R, Nieborowska-Skorska M, Skorski T, BCR-ABL1 kinase facilitates localization of acetylated histones 3 and 4 on DNA double-strand breaks. Leuk Res 36:2(241-4)2012 Feb

21653319. Slupianek A, Dasgupta Y, Ren SY, Gurdek E, Donlin M, Nieborowska-Skorska M, Fleury F, Skorski T, Targeting RAD51 phosphotyrosine-315 to prevent unfaithful recombination repair in BCR-ABL1 leukemia. Blood 118:4(1062-8)2011 Jul 28

21519342. Koptyra M, Stoklosa T, Hoser G, Glodkowska-Mrowka E, Seferynska I, Klejman A, Blasiak J, Skorski T, Monoubiquitinated Fanconi anemia D2 (FANCD2-Ub) is required for BCR-ABL1 kinase-induced leukemogenesis. Leukemia 25:8(1259-67)2011 Aug

21299457. Skorski T, Chronic myeloid leukemia cells refractory/resistant to tyrosine kinase inhibitors are genetically unstable and may cause relapse and malignant progression to the terminal disease state. Leuk Lymphoma 52 Suppl 1:(23-9)2011 Feb

21123451. Slupianek A, Poplawski T, Jozwiakowski SK, Cramer K, Pytel D, Stoczynska E, Nowicki MO, Blasiak J, Skorski T, BCR/ABL stimulates WRN to promote survival and genomic instability. Cancer Res 71:3(842-51)2011 Feb 1

18757400. Cramer K, Nieborowska-Skorska M, Koptyra M, Slupianek A, Penserga ET, Eaves CJ, Aulitzky W, Skorski T, BCR/ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA double-strand break repair. Cancer Res 68:17(6884-8)2008 Sep 1

18413724. Stoklosa T, Poplawski T, Koptyra M, Nieborowska-Skorska M, Basak G, Slupianek A, Rayevskaya M, Seferynska I, Herrera L, Blasiak J, Skorski T, BCR/ABL inhibits mismatch repair to protect from apoptosis and induce point mutations. Cancer Res 68:8(2576-80)2008 Apr 15

18398719. Skorski T, BCR/ABL, DNA damage and DNA repair: implications for new treatment concepts. Leuk Lymphoma 49:4(610-4)2008 Apr

19248582. Pytel D, Slupianek A, Ksiazek D, Skórski T, Blasiak J, [Uracil-DNA glycosylases]. Postepy Biochem 54:4(362-70)2008

20425353. Skorski T, Genomic instability: The cause and effect of BCR/ABL tyrosine kinase. Curr Hematol Malig Rep 2:2(69-74)2007 May

17431132. Rink L, Slupianek A, Stoklosa T, Nieborowska-Skorska M, Urbanska K, Seferynska I, Reiss K, Skorski T, Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells. Blood 110:2(651-60)2007 Jul 15

16785987. Penserga ET, Skorski T, Fusion tyrosine kinases: a result and cause of genomic instability. Oncogene 26:1(11-20)2007 Jan 4

16687921. Nieborowska-Skorska M, Stoklosa T, Datta M, Czechowska A, Rink L, Slupianek A, Koptyra M, Seferynska I, Krszyna K, Blasiak J, Skorski T, ATR-Chk1 axis protects BCR/ABL leukemia cells from the lethal effect of DNA double-strand breaks. Cell Cycle 5:9(994-1000)2006 May

16618731. Nieborowska-Skorska M, Hoser G, Rink L, Malecki M, Kossev P, Wasik MA, Skorski T, Id1 transcription inhibitor-matrix metalloproteinase 9 axis enhances invasiveness of the breakpoint cluster region/abelson tyrosine kinase-transformed leukemia cells. Cancer Res 66:8(4108-16)2006 Apr 15

16527898. Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M, Blasiak J, Skorski T, BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 108:1(319-27)2006 Jul 1

16297667. Slupianek A, Nowicki MO, Koptyra M, Skorski T, BCR/ABL modifies the kinetics and fidelity of DNA double-strand breaks repair in hematopoietic cells. DNA Repair (Amst) 5:2(243-50)2006 Feb 3

16219545. Ren SY, Xue F, Feng J, Skorski T, Intrinsic regulation of the interactions between the SH3 domain of p85 subunit of phosphatidylinositol-3 kinase and the protein network of BCR/ABL oncogenic tyrosine kinase. Exp Hematol 33:10(1222-8)2005 Oct

16135792. Ren SY, Bolton E, Mohi MG, Morrione A, Neel BG, Skorski T, Phosphatidylinositol 3-kinase p85{alpha} subunit-dependent interaction with BCR/ABL-related fusion tyrosine kinases: molecular mechanisms and biological consequences. Mol Cell Biol 25:18(8001-8)2005 Sep

15965906. Trojanek J, Croul S, Ho T, Wang JY, Darbinyan A, Nowicki M, Del Valle L, Skorski T, Khalili K, Reiss K, T-antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51. J Cell Physiol 206:1(35-46)2006 Jan

15782124. Wang JY, Ho T, Trojanek J, Chintapalli J, Grabacka M, Stoklosa T, Garcia FU, Skorski T, Reiss K, Impaired homologous recombination DNA repair and enhanced sensitivity to DNA damage in prostate cancer cells exposed to anchorage-independence. Oncogene 24:23(3748-58)2005 May 26

15750625. Slupianek A, Gurdek E, Koptyra M, Nowicki MO, Siddiqui KM, Groden J, Skorski T, BLM helicase is activated in BCR/ABL leukemia cells to modulate responses to cisplatin. Oncogene 24:24(3914-22)2005 Jun 2

15588951. Slupianek A, Skorski T, NPM/ALK downregulates p27Kip1 in a PI-3K-dependent manner. Exp Hematol 32:12(1265-71)2004 Dec

15492510. Stoklosa T, Slupianek A, Datta M, Nieborowska-Skorska M, Nowicki MO, Koptyra M, Skorski T, BCR/ABL recruits p53 tumor suppressor protein to induce drug resistance. Cell Cycle 3:11(1463-72)2004 Nov

15304390. Nowicki MO, Falinski R, Koptyra M, Slupianek A, Stoklosa T, Gloc E, Nieborowska-Skorska M, Blasiak J, Skorski T, BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks. Blood 104:12(3746-53)2004 Dec 1

14755242. Chipitsyna G, Slonina D, Siddiqui K, Peruzzi F, Skorski T, Reiss K, Sawaya BE, Khalili K, Amini S, HIV-1 Tat increases cell survival in response to cisplatin by stimulating Rad51 gene expression. Oncogene 23:15(2664-71)2004 Apr 8

14559999. Trojanek J, Ho T, Del Valle L, Nowicki M, Wang JY, Lassak A, Peruzzi F, Khalili K, Skorski T, Reiss K, Role of the insulin-like growth factor I/insulin receptor substrate 1 axis in Rad51 trafficking and DNA repair by homologous recombination. Mol Cell Biol 23:21(7510-24)2003 Nov

12813469. Nowicki MO, Pawlowski P, Fischer T, Hess G, Pawlowski T, Skorski T, Chronic myelogenous leukemia molecular signature. Oncogene 22:25(3952-63)2003 Jun 19

12476306. Skorski T, BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability. Oncogene 21:56(8591-604)2002 Dec 9

12411494. Klejman A, Schreiner SJ, Nieborowska-Skorska M, Slupianek A, Wilson M, Smithgall TE, Skorski T, The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J 21:21(5766-74)2002 Nov 1

12185586. Klejman A, Rushen L, Morrione A, Slupianek A, Skorski T, Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene 21:38(5868-76)2002 Aug 29

12044011. Skorski T, Oncogenic tyrosine kinases and the DNA-damage response. Nat Rev Cancer 2:5(351-60)2002 May

12036885. Nieborowska-Skorska M, Hoser G, Kossev P, Wasik MA, Skorski T, Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis. Blood 99:12(4531-9)2002 Jun 15

12024032. Slupianek A, Hoser G, Majsterek I, Bronisz A, Malecki M, Blasiak J, Fishel R, Skorski T, Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. Mol Cell Biol 22:12(4189-201)2002 Jun

11684015. Slupianek A, Schmutte C, Tombline G, Nieborowska-Skorska M, Hoser G, Nowicki MO, Pierce AJ, Fishel R, Skorski T, BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance. Mol Cell 8:4(795-806)2001 Oct

11522649. Nieborowska-Skorska M, Slupianek A, Xue L, Zhang Q, Raghunath PN, Hoser G, Wasik MA, Morris SW, Skorski T, Role of signal transducer and activator of transcription 5 in nucleophosmin/ anaplastic lymphoma kinase-mediated malignant transformation of lymphoid cells. Cancer Res 61:17(6517-23)2001 Sep 1

11280786. Slupianek A, Nieborowska-Skorska M, Hoser G, Morrione A, Majewski M, Xue L, Morris SW, Wasik MA, Skorski T, Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res 61:5(2194-9)2001 Mar 1

10962572. Nieborowska-Skorska M, Slupianek A, Skorski T, Progressive changes in the leukemogenic signaling in BCR/ABL-transformed cells. Oncogene 19:36(4117-24)2000 Aug 24

1857987. Szczylik C, Skorski T, Nicolaides NC, Manzella L, Malaguarnera L, Venturelli D, Gewirtz AM, Calabretta B, Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. Science 253:5019(562-5)1991 Aug 2

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laboratory personnel :

 

Assistant Professors (Research)

Margaret Nieborowska-Skorska, PhD

Artur Slupianek, PhD


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graduate students :

 

Elisabeth Bolton (Program in Microbiology and Immunology)

Kimberly Creamer (Program in Biology)

Yashodara Dasgupta (Program in Biology)

Certain Recent Graduates:

Mandrita Datta, BS, PhD *

Program “Biological and Biomedical Sciences”

Harvard Medical School

Boston, MA

 

Lori Rink, PhD
Fox Chase Cancer Center
Philadelphia, PA

 

Mateusz Koptyra, PhD
Thomas Jefferson University
Jefferson Cancer Center,
Philadelphia, PA


Jolanta Fertala, PhD

Research Associate

Department of Orthopedics

Thomas Jefferson University

Philadelphia, PA


Agata Klejman, PhD

Postdoctoral Fellow

Nencki Institute

Warsaw, Poland


Janina Ratajczak, PhD

Assistant Professor

Department of Medicine

University of Louisville

Louisville, KY


Pawel Wlodarski, PhD

Assistant Professor

Department of Immunology

Medical School

Warsaw, Poland

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grant support :

 

Current or Recent Grant Support of Active Projects:

 

Tomasz Skorski, MD, PhD as Principal Investigator:

5R01CA124014 (Skorski)

Genomic instability causes imatinib resistance in CML

The goal is to identify the role of uracil DNA glycosylase in generation of point mutations and resistance to imatinib in CML and determine if anti-oxidants can prevent this process.

 

1R21CA133646-01A2 (Skorski)

Genome instability in leukemia stem cell

The goal is to identify the sources of reactive oxygen species causing spontaneous DNA damage in leukemia stem cells.

 

3R01CA123014-02S1 (Skorski)

Genomic instability causes imatinib resistance in CML

To purchase Biological Irradiator/Small animal and cell irradiator

 

Temple University bridge grant (Skorski)

RAD51 causes genomic instability in CML

The goal is to target the BCR/ABL-RAD51 interaction to prevent chromosomal aberrations in CML


Tomasz Skorski, MD, PhD as Co-Investigator:

National Institutes of Health, T32 A107101, D. Ganea, PhD, Principal Investigator/Program Director; Microbiology and Immunology Training Program

 

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