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Tomasz Skorski, MD, PhD, DSc

Professor, Microbiology and Immunology

Telephone:  215-707-8847

Fax:  215-707-7788

Email: tomasz.skorski@temple.edu

Department of Microbiology and Immunology

Medical Academy of Warsaw, Poland

 

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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/ABL oncogenic tyrosine kinase produced by the Philadelphia chromosome, and by other FTKs (TEL/ABL, TEL/PDGFβR, TEL/JAK2, NPM/ALK, TEL/TRKC, BCR/FGFR). BCR/ABL gene is derived from relocation of the portion of c-ABL 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/ABL 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.

BCR/ABL exhibits two complementary roles in cancer. The first and best-known, is stimulation of signaling pathways that render cells independent of their environment. BCR/ABL allows cells to proliferate in the absence of growth factors, protects them from apoptosis in the absence of external survival factors, and promotes invasion and metastasis. The second role of BCR/ABL in hematological malignancies, which is just beginning to be recognized fully, is that it can modulate responses to DNA damage, rendering cells to become resistant to genotoxic therapies, and causing genomic instability. Accumulation of mutations is believed to be responsible for the transition from a relatively benign CML chronic phase (CML-CP) to an aggressive blast crisis (CML-BC) and the resistance to imatinib mesylate (IM). BCR/ABL stimulates numerous signaling molecules, including Ras, PI-3k, and STAT5, which are essential not only for leukemogenesis but also for resistance to apoptosis induced by DNA damage. Thus, BCR/ABL-induced pathways seem to play a dual role involving transduction of the signals stimulating transformation and modulation of responses to DNA damage.

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

19657362. Slupianek A, Jozwiakowski SK, Gurdek E, Skorski T, BCR/ABL kinase interacts with and phosphorylates the RAD51 paralog, RAD51B. Leukemia :()2009 Aug 6

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

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

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Assistant Professors (Research)

Margaret Nieborowska-Skorska, PhD

Artur Slupianek, PhD

Assistant Scientist

Shu-yue Ren, PhD

Research Scholar

Pawel Znojek

Visiting Scholar

Dariusz Pytel

Research Technician

Mateusz Koptyra

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E. Bolton (Program in Microbiology and Immunology)

L. Rink (Program in Biology)

K. Creamer (Program in Biology)

M. Bargaoanu (Program in Biology)

Certain Recent Graduates:

Mandrita Datta, BS, PhD *

Program “Biological and Biomedical Sciences”

Harvard Medical School

Boston, MA

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

* Undergraduate student in the Department of Biology, CTS, working under my supervision for more than 3 years, sponsored by Howard Hughes Fellowship for Undergraduate Students

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Current or Recent Grant Support of Active Projects:

Tomasz Skorski, MD, PhD as Principal Investigator:

National Institutes of Health, RO1 CA89052
Role of STAT5 in BCR/ABL Leukemogenesis

 

National Institutes of Health, 1 RO1 CA83700
PI-3K Pathway in BCR/ABL Induced Leukemias

 

American Cancer Society
BCR/ABL - STAT5 Pathways in Leukemogenesis

 

Department of Defense
Does BCR/ABL Induce Self-mutagenesis to Escape Imatinib Mesylate?

 

Department of Defense
The Use of Anti-oxidants as a Therapeutic Tool To Prevent Mutations Causing Imatinib Resistance, and Chromosomal Aberrations Associated with CML Blast Crisis

 

Novartis
Combination of Imatinib Mesylate and Genotoxic Agents in the Treatment of Gliomas and Other Tumors

 

Leukemia and Lymphoma Society Scholarship
Role of DNA Repair/Recombination in Drug Resistance of Leukemia Cells

Tomasz Skorski, MD, PhD as Co-Investigator:

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

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