Tomasz Skorski, MD, PhD, DSc

Tomasz Skorski

Co-Leader, Nuclear Dynamics and Cancer

Director, Fels Cancer Institute for Personalized Medicine

Professor, Department of Cancer and Cellular Biology

Research Program

Educational Background

  • DSc, Medical Center for Postgraduate Education, 1990
  • PhD, Medical Center for Postgraduate Education, 1986
  • MD, Medical Academy of Warsaw, 1982

Research Interests

My laboratory focuses on determination of the role of DNA repair mechanisms in acute (AML, ALL) and chronic (CML) leukemias including the potential of therapeutic interventions. We found that acute and chronic leukemia stem cells (LSCs) accumulate potentially lethal DNA double­ strand breaks (DSBs), but homologous recombination (HR) and non­homologous end­joining (NHEJ) protect their survival. Normal cells use BRAC1/2­dependent  HR and  DNA­PK  –mediated  NHEJ  to  prevent  DSB­triggered  apoptosis.  However,  leukemia  cells  may  employ  RAD52­ mediated HR and PARP1­mediated NHEJ. These changes may be driven by genetic and epigenetic aberrations. Individual patients with leukemias displaying  deficiencies in  specific DSB repair pathway are  identified  by Gene  Expression  and  Mutation  Analysis (GEMA). We  explore  these differences to target tumor­specific DNA repair mechanisms to achieve “synthetic lethality” in leukemia cells, with negligible effects on normal cells. These studies will lead to novel therapeutic approaches based on induction of personalized medicine­guided synthetic lethality in leukemias from individual patients. We were first to demonstrate that targeting RAD52 can be successfully applied in individual leukemias identified by GEMA.

In addition, we examine the role of signaling pathways generating reactive oxygen species (ROS)­induced oxidative stress in CML chronic phase (CML­CP) LSCs and leukemia progenitor cells (LPCs). We were first to show that CML primary cells, including quiescent and proliferating LSCs and proliferating LPCs accumulate high levels of reactive oxygen species (ROS) and oxidative DNA damage, including numerous DNA double strand breaks (DSBs). In addition, we discovered that BCR­ABL1 kinase affects DNA repair pathways: it stimulates unfaithful DSB repair and nucleotide excision repair pathways and inhibits mismatch repair and base excision repair pathways causing genomic instability represented by accumulation of imatinib­resistant BCR­ABL1 kinase mutants and additional chromosomal aberrations. Genomic instability induces CML­CP relapse and/or progression toward more malignant blast phase (CML­BP). Nowadays, most of the CML­CP patients are treated with tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib, which eliminate proliferating cells, but quiescent LSCs are refractory to TKIs. Since TKI­refractory quiescent LSCs accumulate ROS­induced oxidative DNA damage and genetic aberrations causing disease relapse/progression we will develop experimental therapeutic modalities to eradicate these cells.

Additional Publications

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