Nancy A. Speck

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Professor of Cell and Developmental Biology
Department: Cell and Developmental Biology
Graduate Group Affiliations

Contact information
Cell and Developmental Biology
Cancer Biology
511 BRB II/III
Philadelphia, PA 19104
Office: 215-898-0247
Lab: 215-746-5333
Education:
B.A.
Western Maryland College, Westminster, MD, 1977.
Ph.D.
Northwestern University, Evanston IL, 1983.
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Description of Research Expertise

Research Interests
Hematopoietic stem cells and leukemia using mouse models

Key Words
Hematopoietic stem cells, leukemia, core binding factors, transcription, small molecule inhibitors

Research Description
Genes required for blood cell formation and function are often mutated in human leukemia. Excellent examples of this are genes that encode the core binding factors (CBFs), which are heterodimeric transcription factors consisting of a DNA-binding Runx subunit and a non-DNA-binding CBFβ subunit. Our goals are to delineate CBF’s roles during normal embryonic and adult hematopoiesis. This is important for several reasons: 1) Understanding how hematopoiesis occurs in the embryo is essential if we want to ultimately produce blood from embryonic stem cells for stem cell therapy. 2) Characterizing CBF function in adult blood cells is a prerequisite for understanding how mutations in the CBF genes contribute to leukemia.

Inactivating germline mutations in genes encoding either Runx1 (Runx1) or CBFβ (Cbfb) completely eliminate hematopoiesis in the embryo. One important conclusion from these studies was that both the DNA-binding and non-DNA-binding subunits of this CBF complex are essential for its in vivo function. We determined that Runx1 is expressed in a small population of endothelial cells early in mouse development, and appears to be required for the differentiation of hematopoietic stem cells (HSCs) from this “hemogenic” endothelium. Our more recent studies indicate that Runx1 is required in the endothelium per se for HSCs to form. Current research efforts are to define the precise time during embryogenesis at which Runx1 and Cbfb are required for HSC specification and commitment. We also aim to identify the signaling pathways and centers that activate Runx1 expression and hence the hematopoietic program in the embryo.

We are also delineating the role of Runx1 and Cbfb during later stages of hematopoiesis by utilizing conditional and hypomorphic alleles. Using a hypomorphic Cbfb allele, we recently identified a requirement for CBFs at the earliest states of T and natural killer cell development, and are in the process of placing the CBFs in the genetic hierarchy that controls the differentiation of these two lineages. We are also studying the effect of Runx1 deletion in adult HSCs in order to better understand how acquired Runx1 deficiency contributes to leukemogenesis.

RUNX1 (AML1) is disrupted in de novo acute myeloid and lymphocytic leukemias (AML and ALL) and in therapy-related myelodysplasias and leukemias by many chromosomal translocations, the most frequent of which are the t(8;21) and t(12:21) in de novo AML (M2 subtype) and ALL, respectively. Biallelic inactivating mutations in RUNX1 have been found in 20% of AML of the M0 subtype. The CBFB gene is disrupted in AML (M4) by inv(16). Another research goal has been to characterize the biophysical properties of the oncogenic Runx1 and CBFβ fusion proteins found in leukemia, which we have done in the context of a long-standing collaboration with a structural biologist, John Bushweller, at the University of Virginia. Together we have also launched a translational effort to develop small molecule inhibitors of these proteins. We are currently determining which protein-protein interactions mediated by the AML1-ETO protein [which is formed as a result of the t(8;21)] are necessary for its leukemogenic properties, and are developing small molecules to inhibit these interactions.

Lab personnel
Xiongwei Cai, Research Associate
Chung-Tsai Lee, Research Specialist D
Zaw Oo, PhD Student
Joanna Tober, Postdoctoral Fellow
Dana Bellissimo, MDPhD student
Yan Li, Postdoctoral Fellow
Amanda Yzaguirre, PhD Student

Selected Publications

Dzierzak, E.D. and N.A. Speck: Of lineage and legacy: the development of mammalian hematopoietic stem cells. [Review] [107 refs] Nature Immunology 9(2): 129-36, Feb 2008.

North, T., T.-L. Gu, T. Stacy, Q. Wang, L. Howard, M. Binder, M. Marín-Padilla, and N.A. Speck.: Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development 126(11): 2563-75, Jun 1999.

North, T.E., M.F.T.R. de Bruijn, T. Stacy, L. Talebian, E. Lind, C. Robin, M. Binder, E. Dzierzak, and N.A. Speck: Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity 16(5): 661-72, May 2002.

Chen, M., T. Yokomizo, B. Zeigler, N.A. Speck: Runx1 is required for the endothelial to hematopoietic stem cell transition but not thereafter. Nature 457: 887-892 February 2009 Notes: Comments by Yoshomito and Yoder, Nature 457, 801-802; Nature Reports Stem Cells (January 19, 2009); Nature Reports Stem Cells (March 12, 2009); Jaffredo and Dieterlen-Lievre, Cell Stem Cell 4, 189-190.

Guo, Y., I. Maillard, S. Chakraborti, E.V. Rothenberg, and N.A. Speck: Core binding factors are necessary for natural killer cell development and cooperate with Notch signaling during T-cell specification.[see comment]. Blood 112(3): 480-92, Aug 1 2008.

Liu, Y., M. D. Cheney, J.J. Gaudet, M. Chruszcz, S.M. Lukasik, D. Sugiyama, J. Lary, J. Cole, Z. Dauter, W. Minor, N.A. Speck*, J.H. Bushweller*: The tetramer structure of the Nervy homology two domain, NHR2, is critical for AML1/ETO’s activity. Cancer Cell 9: 249-260, April 2006 Notes: (*corresponding authors)

Liu, Y., W. Chen, J. Gaudet, M.D. Cheney, L. Roudaia, T. Cierpicki, R.C. Klet, K. Hartman, T.M. Laue, N.A. Speck*, and J.H. Bushweller*: Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity. Cancer Cell 11(6): 483-97, Jun 2007 Notes: (*corresponding authors).

Gorczynski, M.J., Y. Grembecka, Y. Zhou, Y. Kong, L. Roudaia, M.G. Douvas, M.Newman, G. Baber, IZ. Bielnicka, T. Corpora, J. Shi, M. Sridharan, R. Lilien, B.R. Donald, N.A. Speck, M.L. Brown, J.H. Bushweller: Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta. Chemistry & Biology 14(10): 1186-97, Oct 2007.

Swiers Gemma, de Bruijn Marella, Speck Nancy A: Hematopoietic stem cell emergence in the conceptus and the role of Runx1. The International journal of developmental biology 54(6-7): 1151-63, 2010.

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Last updated: 08/27/2014
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