Associate Professor Hematology and Adjunct Associate Professor Oncological Sciences
Leukemia, Lymphoma, Hematopoietic Stem Cells, Ubiquitination, Proteomics
Molecular Biology Program
B.A. University of St. Thomas - Minnesota
Ph.D. University of Minnesota
The goal of my lab is to utilize genomic and proteomic approaches in normal and malignant hematopoietic cells as well as mouse models to study molecular mechanisms regulating cell fate decisions. Our research specially focuses on studying posttranslational modifications by ubiquitin E3 ligases in self-renewal, differentiation, and transformation. Ubiquitin E3 ligases are the substrate-recognizing component of the UPS that target specific proteins, tags them with polyubiquitin chains, and promotes their degradation through the proteasome. One family of E3 ligases is the FBOX family of proteins, which contains about 71 E3 ligases. To date only 15 of the 71 FBOX proteins have a known role in normal or malignant hematopoiesis. We are currently studying a number of FBOX proteins to understand their role in survival, transformation, and progression of acute myeloid leukemia (AML).
In addition, we are studying the ubiquitin E3 ligase UBR5. UBR5 is mutated in ~18% of patients with Mantle Cell Lymphoma (MCL). Our work has demonstrated a key role of UBR5 in maturation and activation of B cells, and our future goal is to decipher the molecular mechanism of UBR5 in B cell activation and lymphoma. Current and future directions also include utilizing proteomic approaches to identify key proteins expressed in MCL and AML primary patient samples with the goal of identifying potential therapeutic targets. The dynamic reversibility of the ubiquitin modification (by kinases, phosphatases, E3 ligases and de-ubiquitinases) and recent success of a UPS inhibitor (Velcade) for the treatment of hematopoietic malignancies proves the translational importance of the UPS system. The UPS is amenable to molecule targeting, opening the way for possible future therapeutics. Building from our current projects we aim to further explore the role of ubiquitin proteasome system in regulating self-renewal, differentiation, and malignant transformation by utilizing proteomic approaches in normal and malignant hematopoietic populations.
- Wittorf KJ, Weber KK, Swenson SA, Buckley, SM. Ubiquitin E3 ligase FBXO21 regulates cytokine-mediated signaling pathways, but is dispensable for steady-state hematopoiesis. Experimental Hematology, 2022 Aug; 114:33-42.e3. doi:10.1016/j.exphem.2022.08.002. PMID: 35987460 **corresponding author
- Caplan M, Wittorf KJ, Weber KK, Swenson SA, Gilbreath TJ, Hynes-Smith RW, Amador C, Hyde RK, and Buckley SM. Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML. 2022 Feb 17. doi: 10.1038/s41375-022-01518-z. Online ahead of print. **corresponding author
- Swenson, SA, Gilbreath, TJ, Vahle, H, Hynes-Smith, RW, Graham, JH., Law, HCH, Amador, C, Woods, NT, Green, MR, Buckley, SM. UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells. 2020 Jul 16;136(3):299-312. doi:10.1182/blood.2019002102. PMCID: PMC7365918. **corresponding author
- Hynes-Smith RW, Swenson SA, Vahle H, Wittorf KJ, Caplan M, Amador C, Hyde RK, Buckley SM. Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia. Cancers (Basel). 2019 Nov 3;11(11). doi: 10.3390/cancers11111717. PMCID: PMC6895989. **corresponding author