Nancy A. Speck, Ph.D.

faculty photo
John W. Eckman Professor in Medical Science II
Department: Cell and Developmental Biology
Graduate Group Affiliations

Contact information
Cell and Developmental Biology
421 Curie Boulevard
Philadelphia, PA 19104
Office: 215-746-5013
Lab: 215-573-7508
Western Maryland College, Westminster, MD, 1977.
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, inherited leukemia predisposition

Research Description
The work in my laboratory is centered on the core binding factor (Runx1-CBFβ) and its roles in hematopoietic stem cell (HSC) formation and function. We study how HSCs form in the embryo, the step at which HSC formation is dependent on Runx1-CBFβ, the biochemical functions of Runx1-CBFβ, and how mutations in the genes encoding Runx1-CBFβ generate pre-leukemic stem cells. A more recent line of investigation is to determine the role of inflammatory signaling in HSC formation.

I. Hematopoietic stem cell formation in the embryo
A major focus of my laboratory is to understand how hematopoietic stem cells (HSCs) form during normal embryonic development. HSCs and the earlier populations of committed progenitors differentiate from a small, transient population of endothelial cells referred to as “hemogenic endothelium”. About 15 years ago we demonstrated that the transcription factor Runx1 was a specific marker of hemogenic endothelium, and that Runx1 is absolutely required for the formation of blood from hemogenic endothelium (North et al. Development, 1999). We helped settle an almost 100 year debate over whether hemogenic endothelium actually exists, and demonstrated that at least 95% of all adult HSCs are derived from hemogenic endothelium in the embryo (Chen et al. Nature 2009). Another important discovery was that hemogenic endothelium is functionally heterogeneous (Chen et al. Cell Stem Cell, 2011). We more recently discovered a role for sterile inflammatory signaling in HSC formation in the embryo (Li et al. Genes & Development, 2014), and are currently determining which inflammatory pathways are involved.

A transitional cell in HSC formation is the pre-HSC - an immature HSC that has recently differentiated from hemogenic endothelium and remains attached to the arterial wall, and has not yet colonized the fetal liver. The pre-HSC has the potential to become an HSC, but it cannot engraft an adult mouse. It is normally released into the embryonic circulation and matures into a fully functional adult HSC in the fetal liver. We are analyzing the gene expression and chromatin state transitions that underlay the stepwise transition from hemogenic endothelium to pre-HSC to HSC. The goals of this analysis are to identify stage-specific regulatory DNA elements (e.g. promoters and enhancers) that are active (or repressed) during HSC ontogeny, describe the combinatorial patterns associated with various functional DNA elements, and determine the relationship between chromatin state and gene expression through integrative analyses of RNA-Seq and histone modification ChIP-Seq data. We are also attempting to identify new cell surface markers of pre-HSCs.

II. Runx1 mutations in the pre-leukemic stem cell
Runx1 function is absolutely essential for the formation of HSCs in the embryo, but once HSCs colonize the fetal liver they are no longer exquisitely Runx1 dependent (Chen et al. Nature 2009, Tober et al. Development, 2013). However, HSCs containing loss of function (LOF) Runx1 mutations are not normal – they are preleukemic stem cells (pre-LSCs) that are targets for secondary mutations. LOF RUNX1 mutations are common in multiple hematopoietic malignancies including acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelomonocytic leukemia, and in the preleukemic myelodysplastic syndrome.

We are examining the functional consequences of Runx1 LOF mutations, both at a cellular and molecular level. An important discovery was that ribosome biogenesis is decreased in Runx1 deficient HSCs, and that this results in resistance of HSCs to endogenous and genotoxic stress. Ribosome biogenesis in HSCs appears to be directly regulated by Runx1, as Runx1 occupies 80% of ribosome gene promoters and the rDNA gene. We are currently studying how secondary mutations cooperate with Runx1 LOF mutations to regulate ribosome biogenesis, and to contribute to leukemia progression.

Lab personnel
Chung-Tsai Lee, Lab Manager
Joanna Tober, Senior Scientist
Laura Bennett, Postdoctoral Fellow
Suean Fontenard, Postdoctoral Associate
Daniel Yen, MSTP student
Hyun (Claire) An, Graduate Student
Lauren Lavelle, Assistant Director of Administrative & Faculty Affairs

Selected Publications

Zezulin A, Yen D, Ye D, Howell ED, Bresciani E, Diemer J Ren J, Ahmad. MH, Castilla LH, Touw IP, Minn AJ, Tong W, Liu PP, Tan K, Yu W, Speck NA. : RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils. Genes Dev. 37, July 2023.

Howell ED, Yzaguirre AD, Gao P, Lis R, He B, Lakadamyali M, Rafii S, Tan K, Speck NA.: Efficient hemogenic endothelial cell specification by RUNX1 is dependent on baseline chromatin accessibility of RUNX1-regulated TGFβ target genes. Genes Dev 35: 1475-1489, Nov 2021.

Zhu Q, Gao P, Tober J, Bennett L, Chen C, Uzun Y, Li Y, Howell ED, Mumau M, Yu W, He B, Speck NA, Tan K.: Developmental trajectory of prehematopoietic stem cell formation from endothelium. Blood 136: 845-856, Aug 2020.

Bellissimo DC, Chen CH, Zhu Q, Bagga S, Lee CT, He B, Wertheim GB, Jordan M,Tan K, Worthen GS, Gilliland DG, Speck NA: Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling. Blood Adv 4(6): 1145-1158. doi:10.1182/bloodadvances.2019000785. March 2020.

Chen MJ, Li Y, De Obaldia ME, Yang Q, Yzaguirre AD, Yamada-Inagawa T, Vink CS, Bhandoola A. Dzierzak E. Speck NA: Erythroid/myeloid progenitors and hematopoietic stem cells originate from distinct populations of endothelial cells. Cell Stem Cell 9(6): 541-52, Dec 2011.

Chen M, Yokomizo T, Zeigler B, Speck NA: Runx1 is required for the endothelial to hematopoietic stem cell transition but not thereafter. Nature 457: 887-892 Feb 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.

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Last updated: 01/11/2024
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