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Shannon Buckley

Associate Professor Hematology and Adjunct Associate Professor Oncological Sciences

Leukemia, Lymphoma, Hematopoietic Stem Cells, Ubiquitination, Proteomics

 

Buckley

 

Molecular Biology Program

Education

B.A. University of St. Thomas - Minnesota

Ph.D. University of Minnesota

 

Research

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.

References

  1. Dobish KK, Vishwakarma S., Peters HC, Winship CB, Alvarado D, Hyde RK, Natarajan A, Buckley SM. Small molecule targeting of FBXO21 mediated p85α ubiquitylation in acute myeloid leukemia. bioRxiv. 2024.12.13.628427; doi: https://doi.org/10.1101/2024.12.13.628427
  2. Swenson SA, Dobish KK, Peters HC, Winship CB, Hynes-Smith RW, Caplan M, Wittorf KJ, Ghosal G, Buckley SM. Ubiquitin E3 ligase FBXO9 regulates pluripotency by targeting DPPA5 for ubiquitylation and degradation. Stem Cells. 2024 Apr 15;42(4):317-328. doi: 10.1093/stmcls/sxae004 PMID: 38227647; PMCID: PMC11016844.
  3. Dobish KK, Wittorf KJ, Swenson SA, Bean DC, Gavile CM, Woods NT, Ghosal G, Hyde RK, Buckley SM. FBXO21 mediated degradation of p85 regulates proliferation and survival of acute myeloid leukemia. Leukemia. 2023 Nov;37(11):2197-2208. doi: 10.1038/s41375-023-02020-w. Epub 2023 Sep 9. PMID: 37689825; PMCID: PMC10624613.
  4. 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
  5. Caplan M, Wittorf KJ, Weber KK, Swenson SA, Gilbreath TJ, Hynes-Smith RW, Amador C, Hyde RK, Buckley SM. Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML. Leukemia. 2022 May;36(5):1296-1305. doi: 10.1038/s41375-022-01518-z. Epub 2022 Feb 17. PMID: 35177813; PMCID: PMC9061297.
  6. 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. Blood. 2020 Jul 16;136(3):299-312. doi: 10.1182/blood.2019002102. PMID: 32325489; PMCID: PMC7365918
Last Updated: 7/25/25