Shannon M. Buckley

Shannon M. Buckley, PhD

Languages spoken: English

Academic Information

Departments Primary - Internal Medicine , Adjunct - Oncological Sciences

Divisions: Hematology & Hematologic Malignancies

The goal of my lab is to utilize genomic and proteomic approaches in normal and malignant hematopoietic cells 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.

Education History

Fellowship New York University School of Medicine
 Postdoctoral Research Fellow
University of Minnesota
 PhD
Undergraduate University of St. Thomas - Minnesota
 BA

Selected Publications

Journal Article

  1. Wittorf KJ, Weber KK, Swenson SA, Buckley SM (2022). Ubiquitin E3 ligase FBXO21 regulates cytokine-mediated signaling pathways, but is dispensable for steady-state hematopoiesis. Exp Hematol, 114, 33-42.e3. (Read full article)
  2. Ma MCJ, Tadros S, Bouska A, Heavican T, Yang H, Deng Q, Moore D, Akhter A, Hartert K, Jain N, Showell J, Ghosh S, Street L, Davidson M, Carey C, Tobin J, Perumal D, Vose JM, Lunning MA, Sohani AR, Chen BJ, Buckley S, Nastoupil LJ, Davis RE, Westin JR, Fowler NH, Parekh S, Gandhi M, Neelapu S, Stewart D, Bhalla K, Iqbal J, Greiner T, Rodig SJ, Mansoor A, Green MR (2022). Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma. Haematologica, 107(3), 690-701. (Read full article)
  3. Caplan M, Wittorf KJ, Weber KK, Swenson SA, Gilbreath TJ, Willow Hynes-Smith R, Amador C, Hyde RK, Buckley SM (2022). Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML. Leukemia, 2022 May;36(5):1296-1305, 36(5), 1296-1305. (Read full article)
  4. Qiao F, Law HC, Krieger KL, Clement EJ, Xiao Y, Buckley SM, Woods NT (2021). Ctdp1 deficiency leads to early embryonic lethality in mice and defects in cell cycle progression in MEFs. Biol Open, 10(1). (Read full article)
  5. Swenson SA, Gilbreath TJ, Vahle H, Hynes-Smith RW, Graham JH, Law HC, Amador C, Woods NT, Green MR, Buckley SM (2019). UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells. Blood, 136(3), 299-312. (Read full article)
  6. Hynes-Smith RW, Swenson SA, Vahle H, Wittorf KJ, Caplan M, Amador C, Hyde RK, Buckley SM (2019). Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia. Cancers (Basel), 11(11). (Read full article)
  7. Quadros RM, Miura H, Harms DW, Akatsuka H, Sato T, Aida T, Redder R, Richardson GP, Inagaki Y, Sakai D, Buckley SM, Seshacharyulu P, Batra SK, Behlke MA, Zeiner SA, Jacobi AM, Izu Y, Thoreson WB, Urness LD, Mansour SL, Ohtsuka M, Gurumurthy CB (2017). Easi-CRISPR: a robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins. Genome Biol, 18(1), 92. (Read full article)
  8. Strikoudis A, Lazaris C, Trimarchi T, Galvao Neto AL, Yang Y, Ntziachristos P, Rothbart S, Buckley S, Dolgalev I, Stadtfeld M, Strahl BD, Dynlacht BD, Tsirigos A, Aifantis I (2016). Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a. Nat Cell Biol, 18(11), 1127-1138. (Read full article)
  9. Gao J, Buckley SM, Cimmino L, Guillamot M, Strikoudis A, Cang Y, Goff SP, Aifantis I (2015). The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis. Elife, 4. (Read full article)
  10. Khurana S, Margamuljana L, Joseph C, Schouteden S, Buckley SM, Verfaillie CM (2013). Glypican-3-mediated inhibition of CD26 by TFPI: a novel mechanism in hematopoietic stem cell homing and maintenance. Blood, 121(14), 2587-95. (Read full article)
  11. Reavie L, Buckley SM, Loizou E, Takeishi S, Aranda-Orgilles B, Ndiaye-Lobry D, Abdel-Wahab O, Ibrahim S, Nakayama KI, Aifantis I (2011). Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell, 23(3), 362-75. (Read full article)
  12. Khurana S, Buckley S, Schouteden S, Ekker S, Petryk A, Delforge M, Zwijsen A, Verfaillie CM (2012). A novel role of BMP4 in adult hematopoietic stem and progenitor cell homing via Smad independent regulation of integrin-α4 expression. Blood, 121(5), 781-90. (Read full article)
  13. 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, Aifantis I (2012). Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. Cell Stem Cell, 11(6), 783-98. (Read full article)
  14. Buckley SM, Ulloa-Montoya F, Abts D, Oostendorp RA, Dzierzak E, Ekker SC, Verfaillie CM (2010). Maintenance of HSC by Wnt5a secreting AGM-derived stromal cell line. Exp Hematol, 39(1), 114-123.e1-5. (Read full article)
  15. 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, Aifantis I (2010). Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase-substrate complex. Nat Immunol, 11(3), 207-15. (Read full article)
  16. Sahin MB, Schwartz RE, Buckley SM, Heremans Y, Chase L, Hu WS, Verfaillie CM (2008). Isolation and characterization of a novel population of progenitor cells from unmanipulated rat liver. Liver Transpl, 14(3), 333-45. (Read full article)
  17. Serafini M, Dylla SJ, Oki M, Heremans Y, Tolar J, Jiang Y, Buckley SM, Pelacho B, Burns TC, Frommer S, Rossi DJ, Bryder D, Panoskaltsis-Mortari A, OShaughnessy MJ, Nelson-Holte M, Fine GC, Weissman IL, Blazar BR, Verfaillie CM (2007). Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells. J Exp Med, 204(1), 129-39. (Read full article)
  18. Liu B, Buckley SM, Lewis ID, Goldman AI, Wagner JE, van der Loo JC (2003). Homing defect of cultured human hematopoietic cells in the NOD/SCID mouse is mediated by Fas/CD95. Exp Hematol, 31(9), 824-32. (Read full article)
  19. van der Loo JC, Liu BL, Goldman AI, Buckley SM, Chrudimsky KS (2002). Optimization of gene transfer into primitive human hematopoietic cells of granulocyte-colony stimulating factor-mobilized peripheral blood using low-dose cytokines and comparison of a gibbon ape leukemia virus versus an RD114-pseudotyped retroviral vector. Hum Gene Ther, 13(11), 1317-30. (Read full article)

Review

  1. Hynes-Smith RW, Wittorf KJ, Buckley SM (2020). Regulation of Normal and Malignant Hematopoiesis by FBOX Ubiquitin E3 Ligases. [Review]. Trends Immunol, 41(12), 1128-1140. (Read full article)

Book Chapter

  1. Buckley S, Verfaillie C (2011). Regulation of Hematopoiesis. In Porwit A McCullough J, Erber WN (Eds.), Blood and Bone Marrow Pathology (2nd edition, pp. 63-76). Churchill Livingstone: Elsevier.
  2. Lakshmipathy U, Buckley S, Verfaillie C (2007). Gene transfer via nucleofection into adult and embryonic stem cells. In Vemuri MC (Ed.), Stem Cell Assays, Methods Molecular Biology (pp. 407: 115-26). Humana Press.

Abstract

  1. Gilbreath T, Swenson S, Buckley SM (2019). Role of Ubiquitin E3 Ligase UBR5 in B-Cell Development and Lymphoma [Abstract]. 134(Suppl1), 2794.

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