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Michael Engel

Associate Professor of Pediatrics and
Adjunct Associate Professor of Oncological Sciences

Co-Director MD-PhD Training Program

Michael Engel

B.S. Purdue University

M.D. Vanderbilt University School of Medicine

Ph.D. Vanderbilt University School of Medicine



Michael Engel's Lab Page

Michael Engel's PubMed Literature Search

Molecular Biology Program

Leukemia, Hematopoiesis, Transcription


Acute leukemias are life threatening diseases of the bone marrow characterized by accumulation of leukemia cells and failure of normal blood cell development (hematopoiesis). Despite decades of research, drugs used to treat acute leukemias have not changed appreciably in nearly 40 years, and we now have reached the limit of what can be reasonably achieved with these non-selective, cytotoxic agents. To improve outcomes for these patients, new therapeutic targets and strategies are clearly needed. This requires a comprehensive understanding of molecular determinants governing normal and malignant hematopoiesis.

Acute leukemias can be divided into those with lymphoid (ALL) and myeloid (AML) phenotypes, and our group is interested in the pathogenesis of each, as well as development of therapeutic strategies to combat them. Our most recent work focuses on Notch signaling as a critical determinant of the malignant phenotype in both ALL and AML subgroups. Notch receptors bind ligands expressed on adjacent cells, causing release of the Notch intracellular domain (NICD) by proteolytic cleavage. NICD travels to the nucleus to engage partners that control cell fate decisions. Notch acts at multiple points in developmental hematopoiesis, while mutations in Notch or Notch regulators can be found in ~80% of T-cell ALL cases. Understanding NICD partnerships offers insights into how Notch signals control cell fate. We have discovered two NICD binding partners that govern cell fate decisions in normal and malignant hematopoiesis. The first, GFI1, is a zinc finger transcriptional repressor needed for T-cell development, and the second, MTG16, is a transcriptional co-repressor that coordinates multiple aspects of hematopoiesis. We are pursuing these partnerships both to understand their interplay with Notch signaling in developmental hematopoiesis and to serve as platforms for anti-leukemic therapy.

GFI1 is required for early thymocyte progenitors to withstand robust Notch signaling during T-cell development. Likewise, GFI1 is necessary to establish and maintain a malignant phenotype in Notch-driven T-ALL. We have discovered that NICD binds GFI1 directly, blocking GFI1 SUMOylation and polyubiquitination normally required for GFI1 turnover. Thus, NICD stabilizes GFI1 to reinforce its pro-survival role in T-ALL. We hypothesize that GFI1 stabilization represents a critical adaptation to constitutive Notch signaling, making GFI1 effectors logical therapeutic targets in T-ALL. The dominant effector of GFI1-mediated transcriptional repression is LSD1. We are simultaneously delving deeply into the molecular mechanisms behind NICD—GFI1—LSD1 axis function and developing LSD1 inhibitors as candidate T-ALL therapeutic agents.

MTG16 is a master regulator in hematopoiesis, and MTG16-deficient hematopoietic stem-progenitor cells show developmental defects under normal and stress conditions. Moreover, MTG16 undergoes a translocation with RUNX1 in therapy related AML and with GLIS2 in M7-AML unrelated to Down Syndrome. We discovered that MTG16 binds NICD, that a naturally occurring Mtg16 splice variant (MTG16c) fails to do so, and that Notch-driven cell fate in hematopoiesis is altered by MTG16 status. When MTG16 is absent, or when MTG16c is expressed, NICD favors myeloid cell fate that it would otherwise repress. These data suggest MTG16 provides context to Notch signaling in hematopoiesis and intimates a more prominent role for Notch signaling in normal and malignant hematopoiesis.


  1. Velinder M, Singer J, Bareyan D, Meznarich J, Tracy CM, Fulcher JM, McClellan D, Lucente H, Franklin S, Sharma S, and Engel ME. (2016) GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1. Biochem J, 473(19):3355-69. PMID 27480105
  2. Andrade D, Velinder M, Singer J, , Maese L, Bareyan D, Nguyen H, Chandrasekharan M, Lucente H, McClellan D, Jones D, Sharma S, Liu F, and Engel ME. (2016) Sumoylation regulates Growth Factor Independence (GFI) 1 in transcriptional control and hematopoiesis. Mol Cell Biol, 36(10) 1438-1450.PMID 26951200
  3. Fadul J, Bell R, Hoffman LM, Lawlor ER, Beckerle MC, Engel ME and Lessnick SL. (2015) EWS/FLI1 utilizes NKX2-2 to repress mesenchymal features of Ewing Sarcoma. Genes & Cancer, 6(3-4), 129-143. PMID 26000096
  4. Nguyen H, Mariotti J, Bareyan D, Carnahan R, Cooper T, Williams CS and Engel ME. (2015). Anti-MTG16 antibodies reveal MTG16 subcellular distribution and nucleocytoplasmic transport in erythroleukemia cells. Antibody Tech J. 2015(5), 27-41.
  5. Parang B, Rosenblatt D, Williams AD, Washington MK, Revetta F, Short SP, Reddy VK, Hunt A, Shroyer NF, Engel ME, Hiebert SW, and Williams CS. (2015). The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation. FASEB J. 29(3), 786-795. PMID 25398765.
  6. Barrett CW, Smith JJ, Lu LC, Markham N, Stengel KR, Short SP, Zhang B, Hunt AA, Fingleton BM, Carnahan RH, Engel ME, Chen X, Beauchamp RD, Wilson KT, Hiebert SW, Reynolds AB, Williams CS. (2012). Kaiso directs the transcriptional co-repressor MTG16 to the Kaiso binding site in target promoters. PLoS ONE7(12), 1205-1218. PMID 23251453
  7. Hunt A, Fischer M, Engel ME, Hiebert SW. (2011). Mtg16/Eto2 contributes to murine T-cell development. Mol Cell Biol31(13), 2544-51. PMID 21536648
  8. Engel ME, Nguyen HN, Mariotti J, Hunt A, Hiebert SW. (2010). Myeloid translocation gene 16 (MTG16) interacts with Notch transcription complex components to integrate Notch signaling in hematopoietic cell fate specification. Mol Cell Biol30(7), 1852-63. PMID 20123979
  9. Engel ME, Hiebert SW. (2010). The enemy within: Awakening endogenous retroviruses. Nat Med16, 517-518. PMID 20448571
  10. Chyla BJ, Moreno-Miralles I, Steapleton MA, Thompson MA, Bhaskara S, Engel M, Hiebert SW. (2008). Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation. Mol Cell Biol28(20), 6234-47. PMID 18710942
  11. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL. (2001). Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell12(1), 27-36. PMID 11160820

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Last Updated: 5/24/18