In the past 25 years my laboratory was focused on determination of the role of DNA repair mechanisms in acute (AML, ALL) and chronic (CML) leukemias and in myeloproliferative neoplasms (MPNs) including the potential of therapeutic interventions. We found that acute and chronic leukemia stem cells (LSCs I have more than 30 years of experience in studying molecular mechanisms of leukemogenesis.) accumulate potentially lethal DNA double-strand breaks (DSBs), but homologous recombination (HR) and non-homologous end-joining (NHEJ) protect their survival. Normal cells use BRCA1/2-dependent HR and DNA-PK –mediated NHEJ to prevent DSB-triggered apoptosis. However, leukemia cells may employ alternative mechanisms such as RAD52-mediated alternative HR and PARP1/Polq-dependent microhomology-mediated end-joining (MMEJ). These changes may be driven by genetic and epigenetic aberrations (e.g., mutations in TET2 and DNMT3A). We explore these differences to target tumor-specific DNA repair mechanisms to achieve synthetic lethality in leukemia cells, with negligible effects on normal cells. Individual patients with leukemias displaying deficiencies in specific DSB repair pathways and thus sensitive to synthetic lethality triggered by PARP inhibitors were identified by Gene Expression and Mutation Analysis (GEMA). We were first to demonstrate that targeting PARP1 combined with standard therapeutic regimens can be applied in individual leukemias identified by GEMA. These studies led to novel therapeutic approaches based on induction of personalized medicine-guided synthetic lethality in MPNs. Since hematological malignancies are multiclonal, we designed a "clonal medicine" approach to eliminate all malignant clones in AML and MPN patients by targeting specific DNA repair pathways in individual clones. My laboratory received continuous external funding since 1999 from NIH, American Cancer Society, Leukemia and Lymphoma Society, Department of Defense, Leukemia Research Foundation, Elsa U. Pardee Foundation, and When Everybody Survives Foundation.

 As a co-leader of the Nuclear Dynamics and Cancer Program at Fox Chase Cancer Center, I contribute experience in cancer center leadership and program development, with a focus on translational research related to hematological malignancies. In addition, I serve as the Director of Fels Cancer Institute for Personalized Medicine at Temple University Lewis Katz School of Medicine.

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.