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. Adult hematopoiesis is maintained throughout life by the hematopoietic stem cell (HSC), which are self-renewing population capable of generating all hematopoietic lineages. Within the bone marrow (BM) the HSCs are quiescent and can signaled to replenish the hematopoietic system in times of stress. Both intrinsic and extrinsic molecular mechanisms such as cytokine signaling and transcription factors play a key role in quiescence, self-renewal, and differentiation. In addition, the ubiquitin proteasome system (UPS), a key modulator of protein stability and function, regulates cell fate decisions adding an additional layer to molecular mechanisms regulating hematopoiesis. 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 HSC maintenance, differentiation, and malignant transformation.
We also 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. In addition, we have utilized proteomic approaches to identify key proteins expressed in MCL patients 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 multiple myeloma and mantle cell lymphoma proves the translational importance of the UPS system. The UPS is amenable to molecule targeting, opening the way for possible future therapeutics. This suggests that targeting of specific elements of the UPS could lead to future breakthroughs in both basic research and cancer therapy by leading to more efficient generation of induced pluripotent stem cells, promoting lineage differentiation for cell therapy, and provide potential targets for drug discovery. 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 both proteomic and genomic approaches in normal and malignant hematopoietic populations.
Shannon Buckley
Associate Professor
University of Utah
Dept. of Internal Medicine
Div. of Hematology and Hematopoietic Malignancies
Shannon.Buckley@hci.utah.edu
Bea Winship
Lab Manager
University of Utah
Dept. of Internal Medicine
Div. of Hematology and Hematopoietic Malignancies
Bea.Winship@hci.utah.edu
Paulina Jaimes
Graduate Student
University of Utah
Dept. of Oncological Sciences
Div. of Hematology and Hematopoietic Malignancies
Paulina.Jaimes@hci.utah.edu
Kasidy Weber
Assistant Professor
University of Utah
Department of Neurobiology
Kasidy.Weber@hci.utah.edu
Deborah Kajewole, PhD
Postdoctoral Fellow
University of Utah
Dept. of Internal Medicine
Div. of Hematology and Hematopoietic Malignancies
Deborah.Kajewole@hci.utah.edu
Hank Peters
Lab Specialist
University of Utah
Dept. of Internal Medicine
Div. of Hematology and Hematopoietic Malignancies
Hank.Peters@hci.utah.edu
Laura Mims, MD
Medical Fellow
University of Utah
Dept. of Pediatrics
Div. of Hematology and Hematopoietic Malignancies
Laura.Mims@hsc.utah.edu
Danielle Alvarado
Undergraduate Researcher
University of Utah
Dept. of Internal Medicine
Div. of Hematology and Hematopoietic Malignancies
Danielle.Alvarado@hci.utah.edu
Cassandra Burdick
Undergraduate Researcher
University of Utah
Dept. of Internal Medicine
Div. of Hematology and Hematopoietic Malignancies
Cassandra.Burdick@hci.utah.edu
Kate Hansen
Undergraduate Researcher
University of Utah
Dept. of Internal Medicine
Div. of Hematology and Hematopoietic Malignancies
u1304173@utah.edu
Tieker Duncan-Silas
Lab Specialist
current: Medical School
Dalton Bean
Master's Student
current:
Cathy Gaville
Postdoctoral Fellow
current:
Karli Wittorf
PhD Student
current:Assitant Professor, Creighton University
Tyler Gilbreath
PhD Student
current:
Samantha Swenson
Postdoctoral Fellow
current: Instructor at UNMC
Willow Hynes-Smith
PhD 2019
current:
Mika Caplan
Undergraduate Student
current: PhD student UCSD
(Selected Publications Since 2010)
- Swenson SA, Dobish KK, Peters HC, Winship CB, Hynes-Smith RW, Caplan M, Wittorf KJ, Ghosal G, Buckley SM . (2024). Ubiquitin E3 ligase FBXO9 regulates pluripotency by targeting DPPA5 for ubiquitylation and degradation, 2024;, sxae004 . Stem Cells.
- Dobish KK, Wittorf KJ, Swenson SA, Bean, DC, Gavile, CM, Woods NT, Ghosal, G, Hyde RK, Buckley SM . (2023). FBXO21 mediated degradation of p85 regulates proliferation and survival of acute myeloid leukemia. Leukemia. 2023 Nov;37(11):2197-2208.
- 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 114, 33-42 (2022). https://doi.org/10.1016/j.exphem.2022.08.002
- 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. Leukemia 36, 1296–1305 (2022). https://doi.org/10.1038/s41375-022-01518-z
- Hynes-Smith, RW, Wittorf KJ, Buckley, SM. Regulation of normal and malignant hematopoiesis by FBOX ubiquitin E3 ligases. Trends in Immunology. 2020.
- Swenson, SA., Gilbreath, TJ., Vahle, H., Hynes-Smith, RW., Law, HCH., Woods, NT., Green, MR., Buckley, SM. UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells. Blood. 2020;136(3):299-312. doi:10.1182/blood.2019002102.
- Hynes-Smith, RW., Swenson, SA., Vahle, H., Wittorf, KJ., Caplan, Amador, C., Hyde, RK., Buckley, SM. Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia. Cancers 2019, 11(11), 1717; https://doi.org/10.3390/cancers11111717
- Gao, J*, Buckley, SM*, Cimmino L, Guillamot M, Strikoudis A, Cang Y, Goff SP, Aifantis I. The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis. Elife. 2015 Nov 27;4. pii: e07539. doi: 10.7554/eLife.07539. PubMed PMID: 26613412. (*contributed equally to the manuscript)
- Reavie, LR.*, Buckley, SM.*, Loizou, E, Takeishi, S., Abdel-Wahab, O., Aranda-Orgilles, B., Ndiaye-Lobry, D., Ibrahim, S., Nakayama, KI., and Aifantis, I. Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell. 2013; 23(3):362-375. (*contributed equally to the manuscript)
- Buckley, SM., Aranda-Orgilles, B., Strikoudis, A., Apostolou, E., Loizou, E., Moran-Crusio, K., Farnsworth, CL., Koller, AA., Dasgupta, R., Silva, JC., Stadtfeld, M., Hochedlinger, K., Chen, EI., and Aifantis, I. Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. Cell Stem Cell. 2012; 11(6):783-798. Comment in: Cell Stem Cell. 2013; 11(6):728-730. UPS Delivers Pluripotency. Okita, Y. and Nakayama, K.
- Buckley, S. and Verfaillie, C. Regulation of Hematopoiesis. In: Blood and Bone Marrow Pathology, 2nd ed. Elsevier, 63-76, 2011.
- Buckley, SM., Ulloa-Montoya, F., Abts, D., Oostendorp, R., Dzierzak, E., Ekker, SC. and Verfaillie, CM. Maintenance of HSC by Wnt5a secreting AGM-derived stromal cell line. Experimental Hematology. 2011; 39(1):114-123.
- Reavie, L., Della Gatta, G., Crusio, K., Aranda-Orgilles, B., Buckley, SM., Thompson, B., Lee, E., Gao, J., Bredemeyer, AL., Helmink, BA., Zavadil, J., Sleckman, BP., Palomero, T., Ferrando, A., and Aifantis, I. Regulation of Hematopoietic Stem Cell Differentiation by a Single Ubiquitin Ligase-Substrate Complex. Nature Immunology. 2010; 11(3):207-15.
2024
(September) Kasidy defended her thesis! Congratulations Dr. Dobish!
2023
Congratulations Sam, Kasidy, and Karli for their publications in Leukemia and Stem Cells!
2022
(August) Tyler and Karli graduated! Congratulations Dr. Gilbreath and Dr. Wittorf!
(August) Big news, the Buckley Lab moved to the University of Utah in the Huntsman Cancer Institute
(January) Shannon received the Joseph P. and Harriet K. Gilmore Distinguished New Investigator Award and UNMC New Investigator Award
2021
(January) Shannon is selected as 2021 ASH scholar
(July) Dalton and Bea join the lab!
(August) The Buckley Lab is now funded by an NIH NCI R37 and NIAID R01 award!
2020
(December) Willow and Karli publish a review in Trends in Immunology
(December) Kasidy joins the lab
(July) Tyler and Karli are awarded UNMC graduate fellowships
(May) Mika graduates with honors at UNL and is off to start her PhD at UCSD
(April) Sam and Tyler's manuscript is accepted in Blood!
2019
(December) Willow defends her thesis. Congrats, Dr. Hynes-Smith!
We are looking for undergraduate students, graduate students, and postdoctoral fellows interested in studying the role of the ubiquitin proteasome systems in regulating normal and maliganant hematopoiesis. If interested in our research please email me at Shannon.Buckley@hci.utah.edu with your CV and statement of research interests.
