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David Wiest, PhD

David Wiest, PhD
About

Deputy Chief Scientific Officer

Professor

Co-Leader, Blood Cell Development and Function

Research Program

Schematic of role of TCR signaling in fate adoption
Model by which prolonged ERK signals promote adoption of distinct fates
Extraribosomal functions of Rpl22 and Rpl22-like1 (Like1)
Control of hematopoietic stem cell emergence by Rpl22/Like1 antagonism
Antagonistic regulation of RNA splicing by Rpl22 and Like1
Analysis of Bcl11b candidate from a leaky SCID patient

 

Education, Training & Credentials

Educational Background

  • Postdoctoral training, Developmental Immunology, NIH, 1995
  • PhD, Immunology, Duke University, 1991
  • BS, Microbiology, Penn. State University, 1984

Honors & Awards

  • Senior Research Excellence Award, Temple Translational Science Symposium
  • American Cancer Society Southeastern Pennsylvania Research Award
  • Bucks County Board of Associates Key to the Chapter Award
  • Elected to Henry Kunkel Society
  • Inspired Leadership Award
  • Member, Program Committee, American Association of Immunologists
  • Member Faculty of 1000, Leukocyte Development Section
  • Member, CMIB study section
  • Cancer Research Institute Fellow
  • Norman F. Conant Award for Excellence in Research
Research Profile

Research Program

Research Interests

T lymphocyte development and transformation

  • Molecular basis for specification of the two major T lymphocyte lineages, αβ and γδ
  • Regulatory functions of the ribosomal protein Rpl22 in hematopoiesis, lymphoid development, and leukemogenesis
  • Using zebrafish to identify disease-causing genes in immunodeficient humans

Lab Overview

T lymphocyte development and transformation

T lymphocytes recognize and destroy invading pathogens through an assembly of proteins called the T cell antigen receptor (TCR) complex. The TCR has protein subunits that are highly variable and responsible for target recognition (either αβ or γδ) and subunits that are invariant proteins and serve to transmit signals (CD3γδε and ζ). This critical protein assembly (the TCR) controls not only the behavior of mature T lymphocytes but also their development in the thymus. My laboratory seeks to understand how T cell development is controlled by the TCR and how these developmental processes are corrupted during development of cancer. In doing so, we exploit the zebrafish and mouse models, as well as both normal and transformed human hematopoietic cells.

There are two types of T lymphocytes, defined by the TCR variable proteins they employ, αβ and γδ. These two T lineages perform distinct functions in immune responses, but arise from a common immature precursor in the thymus. One of our major research interests is to elucidate the molecular processes that instruct the common precursor to adopt these alternate fates (i.e., αβ or γδ). We have found that the nature of the signal transduced by the TCR plays a key role, with transient TCR signals directing specification of the αβ fate, and sustained signals specifying the γδ fate. The signaling axis whose duration of activity is critical for fate specification is defined as: the extracellular regulated kinase (ERK), which induces early growth response (EGR) transcription factors, that transactive the inhibitor of DNA-binding 3 (ID3) target gene. Activation of the ERK-EGR-ID3 signaling axis specifies the alternative αβ and γδ fate through the graded reduction of the activity of E box DNA binding proteins (E proteins), which are critical regulators of lymphocyte development. Current efforts are focused on understanding this fate specification process by building global three-dimensional genomic regulatory networks assembled around E protein targets that are differentially occupied during fate specification. Because E proteins are well-known tumor suppressors, these efforts inform the etiology of leukemia as well as providing insights into the control of lymphoid development.

Our efforts to understand the molecular basis for αβ/γδ T lineage commitment, led us to identify an unusual molecular effector that plays a critical role in this process, the ribosomal protein, Rpl22. Ribosomal proteins (RP) have historically been viewed as supporting the ribosome’s ability to synthesize proteins; however, emerging evidence suggests that RP, many of which are RNA-binding proteins, can actually play critical regulatory roles that control both normal development and transformation. We have found this to be true for Rpl22. Its function is required for development of αβ lineage T cells, but is dispensable for development of γδ T cells. Moreover, it also regulates the emergence and behavior of hematopoietic stem cells and its loss appears to predispose hematopoietic progenitors, as well as cells in other tissues, to transformation. Of note, the function of Rpl22 as a tumor suppressor is antagonized by its highly homologous (73% identical) ribosomal protein paralog, Rpl22-Like1 (Like1), which promotes development and transformation. Accordingly, developmental outcomes and risk for transformation are controlled by the antagonistic balance of Rpl22 to Like1. These proteins do not appear to regulate development by altering the function of the ribosome, but instead appear to do so by functioning away from the ribosome, by binding particular RNA targets and controlling either their splicing or their translation. Efforts are ongoing to identify the collection of cellular targets through which they function as well as the molecular basis by which such similar proteins as Rpl22 and Like1 exert opposing functions. These studies should inform the etiology of a number of human cancers including acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS), and acute myelogenous leukemia (AML).

Many insights into the molecular control of lymphocyte development have resulted from defining the molecular basis for human immunodeficiencies, including servere combined immunodeficiency (SCID). Accordingly, we combine exome sequencing with screening of candidate genes in zebrafish to identify the gene mutations causing SCID. Using this approach, we have already defined a novel inheritance mechanism in SCID, termed uniparental disomy, where two copies of the same mutated, disease-causing allele were inherited from the mother. Moreover, this approach has also succeeded in identifying four novel SCID genes to date, whose functions are being explored. The role of these genes in the etiology or diagnosis of hematologic malignancies is also being explored.

People

Shawn P. Fahl, PhD

Postdoctoral Fellow

Room: R364
215-728-2968

Noa Greenberg-Kushnir, MD

Visiting Scientist

Room: R364
215-728-2968

Bryan Harris, BS

MD/PhD Student, Temple University

Room: R364
215-728-2968

Suraj Peri, PhD

Assistant Research Professor

Room: R433
215-214-4281

Shuyun Rao, PhD

Research Associate

Room: R364
215-728-2968

Michele Rhodes, BS

Scientific Assistant

Room: R364
215-728-2968

Nehal Solanki-Patel, MS

PhD Student, Drexel University

Room: R364
215-728-2968

Minshi Wang, PhD

Postdoctoral Fellow

Room: R364
215-728-2968

Yong Zhang, MD, PhD

Research Associate

Room: R364
215-728-2968
Publications

Selected Publications

Lee, S.-Y., Coffey, F., Fahl, S.P., Peri, S., Rhodes, M., Cai, K.Q., Carleton, M., Hedrick, S.M., Fehling, H.J., Zúñiga-Pflücker, J.C., Kappes, D.J., and Wiest, D.L. 2014. Non-canonical mode of ERK action controls alternative αβ and γδ T lineage fates. Immunity 41:934–946. PubMed

Coffey, F., Lee, S.-Y., Buus, T.B., Lauritsen, J.-P.H., Wong, G.W., Zúñiga-Pflücker, J.C., Kappes, D.J., and Wiest, D.L. 2014. The TCR ligand-inducible expression of CD73 marks γδ lineage commitment and a metastable intermediate in effector specification. J. Exp. Med. 211:329-43. PubMed

Zhang, Y., Duc, A.-C.E., Rao, S., Sun, X.-L., Bilbee, A.N., Rhodes, M., Li, Q., Kappes, D.J., Rhodes, J., and Wiest, D.L., 2013. Control of hematopoietic stem cell emergence by antagonistic functions of ribosomal protein paralogs. Dev. Cell 24:411-425. PubMed

Rao, S., Lee, S.Y., Gutierrez, A., Perrigoue, J., Thapa, R.J., Tu, Z., Jeffers, J.R., Rhodes, M., Anderson, S., Oravecz, T., Hunger, S.P., Timakhov, R.A., Zhang, R., Balachandran, S., Zambetti, G., Testa, J.R., Look, A.T., and Wiest., D.L. 2012. Inactivation of the ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B. Blood 120:3764-3773. PubMed

Roberts, J.L., Buckley, R.H., Liu, B., Pei, J., Lapidus, A., Peri, S., Wei, Q., Shin, J.,. Parrott, R.E., Dunbrack, R., Testa, J.R., Zhong, X.-P., and Wiest, D.L. 2012. CD45 deficient severe combined immunodeficiency caused by uniparental disomy. PNAS 109:10456-10461. PubMed

Lauritsen, J.P.H., Wong, G.W., Lee, S.Y., Lefebvre, J.M., Ciofani, M., Rhodes, M., Kappes, D.J., Zúñiga-Pflücker, J.C., and Wiest, D.L. 2009. Marked induction of the helix-loop-helix protein Id3 promotes the γδ T cell fate and renders their functional maturation Notch-independent. Immunity 31: 565-575. PubMed

Anderson, S.J., Lauritsen, J.P., Hartman, M.G., Foushee, A.M., Lefebvre, J.M., Shinton, S.A., Gerhardt, B., Hardy, R.R., Oravecz, T., and Wiest, D.L. 2007. Ablation of ribosomal protein L22 selectively impairs αβ T cell development by activation of a p53-dependent checkpoint. Immunity 26:759-772. PubMed

Additional Publications

My NCBI