Shannon Elf

Assistant Professor
Research Summary
Although the genes that drive the development of myeloid blood cancers have largely been defined, there are currently few effective targeted treatment strategies for these diseases. The development of imatinib to treat BCR/ABL-­positive chronic myeloid leukemia remains the only true success story, with the majority of targeted therapies for myeloid malignancies demonstrating unimpressive clinical activity. This illuminates the need to exploit the molecular understanding that has been gained in the last decade through cancer exome sequencing to identify novel therapeutic vulnerabilities in myeloid malignancies. Research in the Elf Lab focuses on identifying unique molecular dependencies in myeloid blood cancers that can be targeted for therapeutic intervention, with the long­-term goal of improving upon current treatment regimens for these diseases. Currently, our work focuses on understanding the role of the unfolded protein response (UPR) in myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). Using molecular, biochemical, and cellular approaches in both in vitro and in vivo models, we aim to dissect the molecular mechanisms underlying UPR activation in specific subsets of MPN and AML, and to use this mechanistic insight to develop rationally designed therapies to target the UPR in these challenging diseases.
Keywords
Leukemia, Acute Myeloid, Myeloproliferative Disorders, Unfolded Protein Response, Targeted Molecular Therapies, Metabolism, Hematopoietic Malignancies, Calreticulin
Education
  • Bowdoin College, Brunswick, ME, A.B. Biology & Music, English minor 05/2003
  • Emory University, Atlanta, GA, Ph.D. Molecular & Systems Pharmacology 07/2013
  • Harvard Medical School / Brigham & Women’s Hospital, Boston, MA, Postdoctoral training Hematology 01/2019
Biosciences Graduate Program Association
Publications
  1. Elf S, Abdelfattah NS, Baral AJ, Beeson D, Rivera JF, Ko A, Florescu N, Birrane G, Chen E, Mullally A. Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. Blood. 2018 02 15; 131(7):782-786. View in: PubMed

  2. Fan J, Lin R, Xia S, Chen D, Elf SE, Liu S, Pan Y, Xu H, Qian Z, Wang M, Shan C, Zhou L, Lei QY, Li Y, Mao H, Lee BH, Sudderth J, DeBerardinis RJ, Zhang G, Owonikoko T, Gaddh M, Arellano ML, Khoury HJ, Khuri FR, Kang S, Doetsch PW, Lonial S, Boggon TJ, Curran WJ, Chen J. Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth. Mol Cell. 2016 12 01; 64(5):859-874. View in: PubMed

  3. Elf S, Lin R, Xia S, Pan Y, Shan C, Wu S, Lonial S, Gaddh M, Arellano ML, Khoury HJ, Khuri FR, Lee BH, Boggon TJ, Fan J, Chen J. Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin. Oncogene. 2017 01 12; 36(2):254-262. View in: PubMed

  4. Elf S, Abdelfattah NS, Chen E, Perales-Patón J, Rosen EA, Ko A, Peisker F, Florescu N, Giannini S, Wolach O, Morgan EA, Tothova Z, Losman JA, Schneider RK, Al-Shahrour F, Mullally A. Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation. Cancer Discov. 2016 Apr; 6(4):368-81. View in: PubMed

  5. Wang J, Luo C, Shan C, You Q, Lu J, Elf S, Zhou Y, Wen Y, Vinkenborg JL, Fan J, Kang H, Lin R, Han D, Xie Y, Karpus J, Chen S, Ouyang S, Luan C, Zhang N, Ding H, Merkx M, Liu H, Chen J, Jiang H, He C. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation. Nat Chem. 2015 Dec; 7(12):968-79. View in: PubMed

  6. Lin R, Elf S, Shan C, Kang HB, Ji Q, Zhou L, Hitosugi T, Zhang L, Zhang S, Seo JH, Xie J, Tucker M, Gu TL, Sudderth J, Jiang L, Mitsche M, DeBerardinis RJ, Wu S, Li Y, Mao H, Chen PR, Wang D, Chen GZ, Hurwitz SJ, Lonial S, Arellano ML, Khoury HJ, Khuri FR, Lee BH, Lei Q, Brat DJ, Ye K, Boggon TJ, He C, Kang S, Fan J, Chen J. 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol. 2015 Nov; 17(11):1484-96. View in: PubMed

  7. Kang HB, Fan J, Lin R, Elf S, Ji Q, Zhao L, Jin L, Seo JH, Shan C, Arbiser JL, Cohen C, Brat D, Miziorko HM, Kim E, Abdel-Wahab O, Merghoub T, Fröhling S, Scholl C, Tamayo P, Barbie DA, Zhou L, Pollack BP, Fisher K, Kudchadkar RR, Lawson DH, Sica G, Rossi M, Lonial S, Khoury HJ, Khuri FR, Lee BH, Boggon TJ, He C, Kang S, Chen J. Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Mol Cell. 2015 Aug 06; 59(3):345-358. View in: PubMed

  8. Chen E, Schneider RK, Breyfogle LJ, Rosen EA, Poveromo L, Elf S, Ko A, Brumme K, Levine R, Ebert BL, Mullally A. Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms. Blood. 2015 Jan 08; 125(2):327-35. View in: PubMed

  9. Fan J, Kang HB, Shan C, Elf S, Lin R, Xie J, Gu TL, Aguiar M, Lonning S, Chung TW, Arellano M, Khoury HJ, Shin DM, Khuri FR, Boggon TJ, Kang S, Chen J. Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect. J Biol Chem. 2014 Sep 19; 289(38):26533-41. View in: PubMed

  10. Shan C, Elf S, Ji Q, Kang HB, Zhou L, Hitosugi T, Jin L, Lin R, Zhang L, Seo JH, Xie J, Tucker M, Gu TL, Sudderth J, Jiang L, DeBerardinis RJ, Wu S, Li Y, Mao H, Chen PR, Wang D, Chen GZ, Lonial S, Arellano ML, Khoury HJ, Khuri FR, Lee BH, Brat DJ, Ye K, Boggon TJ, He C, Kang S, Fan J, Chen J. Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Mol Cell. 2014 Aug 21; 55(4):552-65. View in: PubMed

  11. Shan C, Kang HB, Elf S, Xie J, Gu TL, Aguiar M, Lonning S, Hitosugi T, Chung TW, Arellano M, Khoury HJ, Shin DM, Khuri FR, Boggon TJ, Fan J. Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J Biol Chem. 2014 Aug 01; 289(31):21413-22. View in: PubMed

  12. Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, Gu TL, Aguiar M, Lonning S, Chen H, Mohammadi M, Britton LM, Garcia BA, Aleckovic M, Kang Y, Kaluz S, Devi N, Van Meir EG, Hitosugi T, Seo JH, Lonial S, Gaddh M, Arellano M, Khoury HJ, Khuri FR, Boggon TJ, Kang S, Chen J. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell. 2014 Feb 20; 53(4):534-48. View in: PubMed

  13. Zhao X, Chen A, Yan X, Zhang Y, He F, Hayashi Y, Dong Y, Rao Y, Li B, Conway RM, Maiques-Diaz A, Elf SE, Huang N, Zuber J, Xiao Z, Tse W, Tenen DG, Wang Q, Chen W, Mulloy JC, Nimer SD, Huang G. Downregulation of RUNX1/CBFß by MLL fusion proteins enhances hematopoietic stem cell self-renewal. Blood. 2014 Mar 13; 123(11):1729-38. View in: PubMed

  14. Elf SE, Chen J. Targeting glucose metabolism in patients with cancer. Cancer. 2014 Mar 15; 120(6):774-80. View in: PubMed

  15. Hitosugi T, Zhou L, Fan J, Elf S, Zhang L, Xie J, Wang Y, Gu TL, Aleckovic M, LeRoy G, Kang Y, Kang HB, Seo JH, Shan C, Jin P, Gong W, Lonial S, Arellano ML, Khoury HJ, Chen GZ, Shin DM, Khuri FR, Boggon TJ, Kang S, He C, Chen J. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat Commun. 2013; 4:1790. View in: PubMed

  16. Jin L, Li D, Lee JS, Elf S, Alesi GN, Fan J, Kang HB, Wang D, Fu H, Taunton J, Boggon TJ, Tucker M, Gu TL, Chen ZG, Shin DM, Khuri FR, Kang S. p90 RSK2 mediates antianoikis signals by both transcription-dependent and -independent mechanisms. Mol Cell Biol. 2013 Jul; 33(13):2574-85. View in: PubMed

  17. Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH, Shan C, Dai Q, Zhang L, Xie J, Gu TL, Jin P, Aleckovic M, LeRoy G, Kang Y, Sudderth JA, DeBerardinis RJ, Luan CH, Chen GZ, Muller S, Shin DM, Owonikoko TK, Lonial S, Arellano ML, Khoury HJ, Khuri FR, Lee BH, Ye K, Boggon TJ, Kang S, He C, Chen J. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012 Nov 13; 22(5):585-600. View in: PubMed

  18. Liu Y, Liu F, Yu H, Zhao X, Sashida G, Deblasio A, Harr M, She QB, Chen Z, Lin HK, Di Giandomenico S, Elf SE, Yang Y, Miyata Y, Huang G, Menendez S, Mellinghoff IK, Rosen N, Pandolfi PP, Hedvat CV, Nimer SD. Akt phosphorylates the transcriptional repressor bmi1 to block its effects on the tumor-suppressing ink4a-arf locus. Sci Signal. 2012 Oct 23; 5(247):ra77. View in: PubMed

  19. Huang G, Zhao X, Wang L, Elf S, Xu H, Zhao X, Sashida G, Zhang Y, Liu Y, Lee J, Menendez S, Yang Y, Yan X, Zhang P, Tenen DG, Osato M, Hsieh JJ, Nimer SD. The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations. Blood. 2011 Dec 15; 118(25):6544-52. View in: PubMed

  20. Elf S, Blevins D, Jin L, Chung TW, Williams IR, Lee BH, Lin JX, Leonard WJ, Taunton J, Khoury HJ, Kang S. p90RSK2 is essential for FLT3-ITD- but dispensable for BCR-ABL-induced myeloid leukemia. Blood. 2011 Jun 23; 117(25):6885-94. View in: PubMed

  21. Kang S, Elf S, Lythgoe K, Hitosugi T, Taunton J, Zhou W, Xiong L, Wang D, Muller S, Fan S, Sun SY, Marcus AI, Gu TL, Polakiewicz RD, Chen ZG, Khuri FR, Shin DM, Chen J. p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells. J Clin Invest. 2010 Apr; 120(4):1165-77. View in: PubMed

  22. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J, Gu TL, Polakiewicz RD, Roesel JL, Boggon TJ, Khuri FR, Gilliland DG, Cantley LC, Kaufman J, Chen J. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal. 2009 Nov 17; 2(97):ra73. View in: PubMed

  23. Liu Y, Elf SE, Asai T, Miyata Y, Liu Y, Sashida G, Huang G, Di Giandomenico S, Koff A, Nimer SD. The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior. Cell Cycle. 2009 Oct 01; 8(19):3120-4. View in: PubMed

  24. Sashida G, Liu Y, Elf S, Miyata Y, Ohyashiki K, Izumi M, Menendez S, Nimer SD. ELF4/MEF activates MDM2 expression and blocks oncogene-induced p16 activation to promote transformation. Mol Cell Biol. 2009 Jul; 29(13):3687-99. View in: PubMed

  25. Kang S, Elf S, Dong S, Hitosugi T, Lythgoe K, Guo A, Ruan H, Lonial S, Khoury HJ, Williams IR, Lee BH, Roesel JL, Karsenty G, Hanauer A, Taunton J, Boggon TJ, Gu TL, Chen J. Fibroblast growth factor receptor 3 associates with and tyrosine phosphorylates p90 RSK2, leading to RSK2 activation that mediates hematopoietic transformation. Mol Cell Biol. 2009 Apr; 29(8):2105-17. View in: PubMed

  26. Liu Y, Elf SE, Miyata Y, Sashida G, Liu Y, Huang G, Di Giandomenico S, Lee JM, Deblasio A, Menendez S, Antipin J, Reva B, Koff A, Nimer SD. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell. 2009 Jan 09; 4(1):37-48. View in: PubMed

  27. Huang G, Zhang P, Hirai H, Elf S, Yan X, Chen Z, Koschmieder S, Okuno Y, Dayaram T, Growney JD, Shivdasani RA, Gilliland DG, Speck NA, Nimer SD, Tenen DG. PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nat Genet. 2008 Jan; 40(1):51-60. View in: PubMed

  28. McBride AE, Zurita-Lopez C, Regis A, Blum E, Conboy A, Elf S, Clarke S. Protein arginine methylation in Candida albicans: role in nuclear transport. Eukaryot Cell. 2007 Jul; 6(7):1119-29. View in: PubMed

  29. Bassères DS, Levantini E, Ji H, Monti S, Elf S, Dayaram T, Fenyus M, Kocher O, Golub T, Wong KK, Halmos B, Tenen DG. Respiratory failure due to differentiation arrest and expansion of alveolar cells following lung-specific loss of the transcription factor C/EBPalpha in mice. Mol Cell Biol. 2006 Feb; 26(3):1109-23. View in: PubMed

  30. Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno S, Arinobu Y, Geary K, Zhang P, Dayaram T, Fenyus ML, Elf S, Chan S, Kastner P, Huettner CS, Murray R, Tenen DG, Akashi K. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood. 2005 Sep 01; 106(5):1590-600. View in: PubMed