Basic and clinical research are integral to the mission of the Division of Hematology-Oncology. Bringing the best of medical science to clinical practice is a major goal at UT Southwestern Medical Center, and the Division’s physicians undertake a broad range of both clinical and basic research.
The laboratory of Pier Paolo Scaglioni, M.D., whose interests lie in gaining insights into the processes that underlie tumor initiation, progression and maintenance, recently had breakthrough research published in Cancer Research and EMBO Molecular Medicine.
Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence. Scaglioni PP, Rabellino A, Yung TM, Bernardi R, Choi S, Konstantinidou G, Nardella C, Cheng K, Pandolfi PP. EMBO Mol Med. 2012 Feb 22. doi: 10.1002/emmm.201200233.
Oncogene induced premature cellular senescence (OIS) is a critical tumor suppressor mechanism that induces a permanent proliferative arrest. Therefore, therapeutic interventions that affect OIS may significantly impact response to cancer therapy. In this work we report that the promyelocytic tumor suppressor (PML), a critical inducer of cellular senescence, is upregulated by oncogenic K-RAS through translational dependent mechanisms that require mTOR, eIF4E and the PML 5’ untranslated region. Thus far, induction of OIS has been largely attributed to transcriptional mechanisms. Thus, these findings unveil a novel mechanism regulating OIS. Moreover, this data raise the concern that inhibitors of the PI3K/mTOR pathway, which are developed as targeted cancer drugs, may blunt OIS causing unexpected and counterproductive effects in cancer patients.
The SUMO E3-ligase PIAS1 Regulates the Tumor Suppressor PML and Its Oncogenic Counterpart PML-RARA. Rabellino A, Carter B, Konstantinidou G, Wu SY, Rimessi A, Byers LA, Heymach JV, Girard L, Chiang CM, Teruya-Feldstein J, Scaglioni PP. Cancer Res. 2012 May 1;72(9):2275-2284. Epub 2012 Mar 9.
The role of SUMOylation in tumorigenesis and in determining the therapeutic response to cancer therapy is poorly understood. In this manuscript, we report that the SUMO E3 ligase PIAS1 regulates oncogenic signaling through its ability to SUMOylate PML and the PML-RARA oncoprotein of acute promyelocytic leukemia (APL). We found that PIAS1 is overexpressed in lung cancer cells where it promotes the ubiquitin-mediated degradation of PML, attenuating its tumor suppressor functions. We also determined that PIAS1 is essential for the induction of PML-RARA degradation by arsenic trioxide. Arsenic trioxide is a drug of choice for the treatment of APL due to its ability to lead to a SUMO-dependent degradation of PML-RARA, which leads to leukemia remission. These results demonstrate that PIAS1 is the critical therapeutic target in APL. These findings reveal a novel role for PIAS1 and the SUMOylation machinery in regulating oncogenic networks and the response to leukemia therapy.
The Division of Hematology-Oncology’s clinical research program is closely coordinated with the Clinical Research Office of the Harold C. Simmons Comprehensive Cancer Center. Physicians and fellows in the Division of Hematology-Oncology actively recruit patients who meet certain eligibility criteria to a number of ongoing clinical trials. For a complete listing of open studies, please visit the Simmons Cancer Center's Clinical Research Office or the UT Southwestern Clinical Trials Office.
The Division of Hematology Oncology has an active and growing basic research program. Faculty members are appointed jointly in the Graduate School of Biomedical Sciences and train graduate students, post-doctoral fellows, and clinical fellows for careers in biomedical science. For details about individual investigators please visit our Faculty Labs page.