Description of Research Expertise

Research Interests
Tumor Biology, Development, Stem Cells, Hematopoiesis, Immune Function

Research Techniques: In vivo and in vitro models of hematopoiesis, transformation and immunity, retroviral transduction, bone marrow transplantation, ES cell culture and differentiation, cDNA cloning, cell sorting, video microscopy, knockout and RNAi technology, ChIP-Seq and global transcription analysis

Description of Research
A major area of interest of this laboratory is understanding the processes that lead to the development and differentiation of mature hematopoietic cells from a single hematopoietic stem cell. We are particularly interested in studying the processes that perturb these normal processes and cause leukemia. A primary focus of the laboratory is the role that Notch proteins play in regulating hematopoietic cell fate decisions and cancer. Notch proteins are a conserved family of receptors that regulate cell fate decisions in organisms ranging from Drosophila to humans. Using a variety of in vitro and in vivo approaches, we have shown that Notch proteins are key regulators of multiple hematopoietic cell fates. These include establishment of the T cell lineage and helper type 2 T cells. We are presently undertaking studies to identify the signaling pathways that control these and other cell fate decisions in hematopoiesis. In addition to their role in normal hematopoiesis, dysregulation of Notch signaling is a cause of human leukemia. We have developed a mouse model of Notch-related leukemia and are using this to study the signaling pathways that lead to oncogenic transformation. Using gene array and bioinformatics approaches, we have identified several direct transcriptional targets of Notch signaling that appear to mediate its effects in normal development and leukemia. In addition, we are developing and testing ways to block Notch signaling that may be useful in treating leukemia and other Notch-dependent diseases.

Rotation Projects
1. Characterization of Notch transcriptional targets in hematopoiesis and leukemia. This project will characterize potential direct transcriptional targets of Notch signaling that we have identified in a microarray screen. The project will involve verifying that these are direct transcriptional targets using chromatin immunoprecipitation (ChIP), EMSA, and reporter assays and then testing whether these targets are functionally important using retroviral transduction, apoptosis, proliferation, and differentiation in both primary and established cell lines.

2. Identification of genes that potentiate Notch transforming activity. We have induced a number of Notch T cell leukemias using retroviruses that express activated forms of Notch1. The retroviral vectors also contain enhancer elements that can activate transcription of genes in the vicinity of their integration site. We have established techniques to rapidly clone the genes that are activated by retroviral vector integration and will use both in vitro and in vivo assays to determine if they synergize with Notch to induce leukemia.

3. We have identified Tribbles as a novel oncogene in acute myelogenous leukemia. Very little is know about Tribbles function. This project will use biochemical and functional assays to determine the function of Tribbles in leukemia and normal hematopoietic development.

Lab personnel:
Katherine Forsyth, Graduate Student
Ethan Mack, Graduate Student
Vicki Mercado, Post-baccalaureate Scholar
Caitlin O'Neill, Administrative Assistant
Yumi Ohtani, Senior Research Investigator
Jelena Petrovic, Postdoctoral Fellow
Kelly Rome, Graduate Student
Sarah Stein, Postdoctoral Fellow
Lanwei Xu, Research Specialist/Lab Manager

Selected Publications

McClory SE, Bardhan O, Rome KS, Giles JR, Baxter AE, Xu L, Gimotty PA, Faryabi RB, Wherry EJ, Pear WS, Jordan MS.: The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR(+) CD8(+) effector state, and its deletion improves checkpoint blockade Cell Rep 42 : 112905,2023.

Li T, Bou-Dargham MJ, Fultang N, Li X, Pear WS, Sun H, Chen YH.: c-Rel-dependent monocytes are potent immune suppressor cells in cancer J Leukoc Biol : 2022.

Gómez Atria D, Gaudette BT, Londregan J, Kelly S, Perkey E, Allman A, Srivastava B, Koch U, Radtke F, Ludewig B, Siebel CW, Ryan RJ, Robertson TF, Burkhardt JK, Pear WS, Allman D, Maillard I.: Stromal Notch ligands foster lymphopenia-driven functional plasticity and homeostatic proliferation of naïve B cells J Clin Invest : 2022.

Zhou Y, Petrovic J, Zhao J, Zhang W, Bigdeli A, Zhang Z, Berger SL, Pear WS, Faryabi RB.: EBF1 nuclear repositioning instructs chromatin refolding to promote therapy resistance in T leukemic cells Mol Cell 82 (5): 1003-1020,2022.

Schwartz GW, Zhou Y, Petrovic J, Pear WS, Faryabi RB.: TooManyPeaks identifies drug-resistant-specific regulatory elements from single-cell leukemic epigenomes Cell Rep 36 : 109575,2021.

Zheng Q, Capell BC, Parekh V, O'Day C, Atillasoy C, Bashir HM, Yeh C, Shim EH, Prouty SM, Dentchev T, Lee V, Wushanley L, Kweon Y, Suzuki-Horiuchi Y, Pear W, Grice EA, Seykora JT.: Whole-Exome and Transcriptome Analysis of UV-Exposed Epidermis and Carcinoma In Situ Reveals Early Drivers of Carcinogenesis J Invest Dermatol 141 : 295-307,2021.

Kobia FM, Preusse K, Dai Q, Weaver N, Hass MR, Chaturvedi P, Stein SJ, Pear WS, Yuan Z, Kovall RA, Kuang Y, Eafergen N, Sprinzak D, Gebelein B, Brunskill EW, Kopan R.: Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation PLoS Biol 18 : e3000850,2020.

Zhang W, Pear WS.: MYC degradation via AURKB inhibition: a new brake in the path to T-ALL Blood Sci 2 : 68-69,2020.

Rome KS, Stein SJ, Kurachi M, Petrovic J, Schwartz GW, Mack EA, Uljon S, Wu WW, DeHart AG, McClory SE, Xu L, Gimotty PA, Blacklow SC, Faryabi RB, Wherry EJ, Jordan MS, Pear WS.: Trib1 regulates T cell differentiation during chronic infection by restraining the effector program J Exp Med 217 : e20190888,2020.

Schwartz Gregory W, Zhou Yeqiao, Petrovic Jelena, Fasolino Maria, Xu Lanwei, Shaffer Sydney M, Pear Warren S, Vahedi Golnaz, Faryabi Robert B: TooManyCells identifies and visualizes relationships of single-cell clades. Nature Methods 17 (4): 405-413,2020.

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Academic Contact Information

556 BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104-6160
Phone: 215-573-7764