David Wiest, PhD

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About
Education and Training
Research Profile
Lab Staff
Publications

About

Deputy Chief Scientific Officer

Professor

Co-Leader, Blood Cell Development and Function

Colorectal and SI Cancer TRDG Member

Leukemia and MDS TRDG Member

Lymphoma and CLL Cancer TRDG Member

Director, Cell Sorting Facility

Research Program

Blood Cell Development and Function

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 and Training

Educational Background

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

Honors & Awards

NCI Board of Scientific Counselors
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

Blood Cell Development and Function

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... Expand

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. Collapse

Scientific Assistant

Room: R364

215-728-2968

Michele.Rhodes@fccc.edu

Publications

Selected Publications

Rao, S., Peri, S., Hoffman, J., Cai, K.Q., Harris, B., Rhodes, M., Connolly, D.C., Testa, J.R., and Wiest, D.L. 2019. Rpl22L1 overexpression confers 5-FU resistance in colorectal cancer. PLOS One 14:e0222392. PMC6776433

Fahl, S.P., Coffey, F., Kain, L., Zarin, P., Teyton, L., Zúñiga-Pflücker, J.C., Kappes, D.J., and Wiest, D.L. 2018. Role of a selecting ligand in shaping the gd TCR repertoire. PNAS 115:1889-1894. PMC5828614

Fahl SP, Wiest DL. 2018. Reply to Chien: Clarification of the effect of ligand on γδ-TCR repertoire selection. PNAS 115:E3607-E3608. PMC5910880

Tyner, J.W., Tognon, C.E., Bottomly, D., Wilmot, B., Kurtz, S.E., Savage, S.L., Long, N., Schultz, A.R., Traer, E., Abel, M., Agarwal, A., Blucher, A., Borate, U., Bryant, J., Burke, R., Carlos, A., Carpenter, R., Carroll, J., Chang, B.H., Coblentz, C., d'Almeida, A., Cook, R., Danilov, A., Dao, K.T., Degnin, M., Devine, D., Dibb, J., Edwards, D.K. 5th, Eide, C.A., English, I., Glover, J., Henson, R., Ho, H., Jemal, A., Johnson, K., Johnson, R., Junio, B., Kaempf, A., Leonard, J., Lin, C., Liu, S.Q., Lo, P., Loriaux, M.M., Luty, S., Macey, T., MacManiman, J., Martinez, J., Mori, M., Nelson, D., Nichols, C., Peters, J., Ramsdill, J., Rofelty, A., Schuff, R., Searles, R., Segerdell, E., Smith, R.L., Spurgeon, S.E., Sweeney, T., Thapa, A., Visser, C., Wagner, J., Watanabe-Smith, K., Werth, K., Wolf, J., White, L., Yates, A., Zhang, H., Cogle, C.R., Collins, R.H., Connolly, D.C., Deininger, M.W., Drusbosky, L., Hourigan, C.S., Jordan, C.T., Kropf, P., Lin, T.L., Martinez, M.E., Medeiros, B.C., Pallapati, R.R., Pollyea, D.A., Swords, R.T., Watts, J.M., Weir, S.J., Wiest, D.L., Winters, R.M., McWeeney, S.K., Druker, B.J. 2018. Functional genomic landscape of acute myeloid leukaemia. Nature 562:526-531. PMC6280667

Wiest, D.L. 2018. Gadd45 stress sensors in suppression of leukemia. Oncotarget 28:34191-34192. PMC6188131

Isoda, T., Moore, A.J., He, Z., Chandra,V., Aida, M., Denholtz, M., van Hamburg, J.P., Fisch, K.M., Chang, A.N., Fahl, S., Wiest, D.L., Murre, C. 2017. Non-Coding RNA ThymoD Regulates Compartmentalization and Chromatin Folding to Orchestrate T Cell Fate. Cell 171:103-119. PMC5621651

Somech, R., Lev, A., Lee, Y.N., Simon, A.J., Barel, O., Schiby, G., Avivi, C., Barshack, I., Rhodes, M., Yin, J., Wang, M., Yang, Y., Rhodes, J., Marcus, N., Garty, B.-Z., Stein, J., Amariglio, N., Rechavi, G., Wiest, D.L*, and Zhang, Y*. 2017 Disruption of thrombocyte and T lymphocyte development by a mutation in ARPC1B. J. Immunol. 199:4036-4045. * - co-corresponding authors; PMC5726601

Wiest, D.L. 2017. Themis-tery is solved. Nat. Immunol., 18: 368-370. PubMed

Zhang, Y., O’Learly, M.N., Peri, S., Zha, J., Melov, S., Kappes, D.J., Feng, Q., Rhodes, J., Amieux, P.S., Morris, D.R., Kennedy, B.K., and Wiest, D.L. 2017. Ribosomal proteins Rpl22 and Rpl22l1 control morphogenesis by regulating pre-mRNA splicing. Cell Reports 18:545-556. PMC5234864

Fahl, S.P., Coffey, F., MacCormick, D, and Wiest, D.L. 2016. Control of T cell development by TCR signals. Encyclopedia of Immunology Vol. 1:234–241. PubMed

Fahl, S.P., Kappes, D.J., and Wiest, D.L. 2016. TCR signaling circuits in αβ/γδ T lineage choice. In, CRC Methods in Signal Transduction: T cell diversity and function. CRC Press. Editors: Jonathan Soboloff and Dietmar J. Kappes. PubMed

Punwani, D.*, Zhang, Y.*, Yu, J., Cowan, M.J., Kwan, A., Mendelsohn, B.A., Sunderam, U. Srinivasan, R., Brenner, S., Wiest, D.L.*, and Puck, J.M.* 2016. Bcl11b defect in human severe combined immunodeficiency with multisystem anomalies. NEJM 375:2165-2176. PMC5215776 *Contributed equally; Selected for preview; Nominated to F1000. PubMed

Rao, S., Cai, K.Q., Stadanlick, J.E., Greenberg-Kushnir, N., Solanki-Patel, N., Lee, S.-Y., Testa, J.R., and Wiest, D.L. 2016. Ribosomal protein Rpl22 controls the dissemination of T cell Lymphoma. Cancer Research 76:3387-3396. PMC4891229

Simon, A.J., Lev, A., Zhang, Y., Weiss, B., Rylova, A., Eyal, E., Kol, N., Barel, O., Cesarkas, K., Soudack, M., Greenberg-Kushnir, N., Rhodes, N., Wiest, D.L., Schiby, G., Barshack, I., Katz, S., Pras, E., Poran, H., Reznik-Wolf, H., Ribakovsky, E., Simon, C., Hazou, W., Sidi, Y., Lahad, A., Katzir, H., Glousker, G., Amariglio, N., Tzfati, Y., Selig, S., Rechavi, G., and Somech, R. 2016. Mutations in stn1 cause coats plus syndrome and are associated with genomic and telomere defects. J. Exp. Med. 213:1429-1440. PMC4986528

Solanki, N.R., Stadanlick, J.E., Zhang, Y., Duc, A.-C., Lee, S.-Y., Lauritsen, J.P.H., Zhang, Z., and Wiest, D.L. 2016. Rpl22 loss selectively impairs αβ T cell development by dysregulating ER stress signaling. J. Immunol. 197:2280-9. PMC5011012 Highlighted in “In This Issue”. PubMed... Expand

Wiest, D.L. 2016. Development of γδ T cells, the Special Forces Soldiers of the Immune System. Methods in Molecular Biology 1323:23-32. PubMed

Zhang, Y. and Wiest D.L. 2016. Using the zebrafish model to study T cell development. Methods in Molecular Biology 1323:273-292. PubMed

Fahl, S.P., Harris, B., and Wiest, D.L. 2015. Rpl22 loss impairs the development of B lymphocytes by activating a p53-dependent checkpoint. J. Immunol. 194:200-209. PMC4333014

Fahl, S.P., Wang, M. Zhang, Y., and Wiest, D.L. 2015. Regulatory Roles of Rpl22 in Hematopoiesis: An Old Dog With New Tricks. Critical Reviews in Immunology 35:379-399. PMC5111805

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 gd lineage commitment and a metastable intermediate in effector specification. J. Exp. Med. 211:329-43. PMC3920555

Fahl, S.P., Coffey, F., and Wiest, D.L. 2014. Origins of γδ T Cell Effector Subsets: A Riddle Wrapped in an Enigma. J. Immunol. 193:4289-94.

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. PMC4273651

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. PMC3586312 (Highlighted in the Feb. 25, 2013 issue and selected for Faculty of 1000) 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. PMC3488889

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. PMC3387083

Stadanlick, J.E., Zhang, Z., Lee, S.-Y., Hemann, M., Biery, M., Carleton, M.O., Zambetti, G.P., Anderson, S.J., Oravecz, T., and Wiest, D.L. 2011. Developmental arrest of T cells in Rpl22-deficient mice is dependent upon multiple p53 effectors. J. Immunol. 187:664-6775. PMC3131471

Lee, S.-Y., Stadanlick, J., Kappes, D.J., and Wiest, D.L. 2010. Towards a molecular understanding of the differential signals regulating ab/gd T lineage choice. Sem. Immunol. 22:237-246. PMC2906684

Wiest, D.L. 2010. Origins of gdT cells: a forum for opposing perspectives. Editorial. Sem. Immunol. 22:191-192.

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 gd T cell fate and renders their functional maturation Notch-independent. Immunity 31: 565-575. PMC2768560

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 ab T cell development by activation of a p53-dependent checkpoint. Immunity 26:759-772. (Selected for preview by Immunity and selected for Faculty of 1000) PubMed

Ciofani, M. Knowles, G.C., Wiest, D.L., von Boehmer, H., and Zúñiga-Pflücker, J.C. 2006. Stage-specific and differential dependency at the ab/gd T lineage bifurcation branchpoint. Immunity 25:105-16. PubMed

Yamasaki, S., Ishikawa, E., Sakuma, M., Ogata, K., Sakata-Sogawa, K., Hiroshima, M., Wiest, D.L., Tokunaga, M., and Saito, T. 2006. Mechanistic basis of pre-T cell receptor-mediated autonomous signaling critical for thymocyte development. Nature Immunology 7:67-75. PubMed

Haks, M.C., Lefebvre, J.M., Lauritsen, J.P.H., Carleton, M.O., Rhodes, M., Kappes, D.J., and Wiest, D.L. 2005. Attenuation of γδTCR Signaling Efficiently Diverts Thymocytes to the αβ Lineage. Immunity 22: 595-606. (Selected for preview by Immunity, selected for Faculty of 1000, and highlighted by Nature Immunology and Nature Signaling Gateway) PubMed

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Additional Publications

My NCBI

Contact Information

David.Wiest@fccc.edu
Office Phone: 215-728-2966
Lab Phone: 215-728-2968
Fax: 215-728-2412
Office: 383A
Lab: R364

Contact Information

David.Wiest@fccc.edu
Office Phone: 215-728-2966
Lab Phone: 215-728-2968
Fax: 215-728-2412
Office: 383A
Lab: R364

Deputy Chief Scientific Officer

Professor

Co-Leader, Blood Cell Development and Function

Colorectal and SI Cancer TRDG Member

Leukemia and MDS TRDG Member

Lymphoma and CLL Cancer TRDG Member

Director, Cell Sorting Facility

Research Program

Blood Cell Development and Function

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

Educational Background

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

Honors & Awards

NCI Board of Scientific Counselors
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 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

Extramural Affiliations

External News