About

Warren S. Pear, M.D., Ph.D., is the Gaylord P. and Mary Louise Harnwell Professor at the University of Pennsylvania and a member of the Abramson Cancer Center. He is an attending physician in Molecular Pathology within the Center for Personalized Diagnostics. His research focuses on tumor biology, development, stem cells, hematopoiesis, and immune function. His laboratory investigates the processes that lead to the development and differentiation of mature hematopoietic cells from a single hematopoietic stem cell, with particular interest in how perturbations in these processes can cause leukemia. A primary focus of his work is the role of Notch proteins in regulating hematopoietic cell fate decisions and cancer, including establishing the T cell lineage and helper T cell types. His research employs various in vivo and in vitro models, gene array, and bioinformatics approaches to identify transcriptional targets of Notch signaling and develop strategies to block Notch signaling for therapeutic purposes. Pear's contributions include developing mouse models of Notch-related leukemia and studying the signaling pathways involved in oncogenic transformation, with ongoing projects aimed at characterizing transcriptional targets, identifying genes that potentiate Notch's transforming activity, and exploring the function of novel oncogenes such as Tribbles in leukemia and hematopoietic development.

Research topics

• Biology
• Cell biology
• Cancer research
• Immunology
• Molecular biology

Selected publications

• 3137 – CELL FREE TARGETED THERAPY FOR T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

  Experimental Hematology · 2024-08-01

  article
  PublisherDOI

• Supplementary Figure Legends 1-2 from Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes

  2023-03-30

  preprintOpen access

  Supplementary Figure Legends 1-2 from Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes

  PublisherDOI

• Supplementary Tables S1 - S8 from Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma

  2023-04-03

  supplementary-materialsOpen access

  <p>Table S1: Analysis of Notch gene rearrangements in triple negative breast cancer subtypes. Table S2: Genes whose expression correlates with Notch gene-rearrangement status in cancer cell lines. Table S3: Genes whose expression correlates with Notch gene-rearrangement in triple negative breast cancer. Table S4. Novel mutations identified in the NRR and PEST domains of NOTCH1 in solid tumors. Table S5: Notch NRR and PEST domain mutation frequency. Table S6: NOTCH1 mutational status, N1-ICD levels, MYC expression in Adenoid Cystic Carcinoma models. Table S7: Primary antibodies. Table S8: RT-PCR Primers.</p>

  PublisherOA PDFDOI

• Supplementary Table S9 from Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma

  2023-04-03

  supplementary-materialsOpen access

  <p>human Breast tumor Notch gene coverage annotations.</p>

  PublisherDOI

• Data from Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes

  2023-03-30

  preprintOpen access

  <div>Abstract<p>The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (N<sup>IC</sup>) was exploited to determine if Notch activation is a “driving” event in melanocytic transformation or instead a “passenger” event associated with melanoma progression. N<sup>IC</sup>-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. N<sup>IC</sup>-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease. [Cancer Res 2009;69(13):5312–20]</p></div>

  PublisherDOI

• Supplementary Figure Legends 1-2 from Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes

  2023-03-30

  preprintOpen access

  Supplementary Figure Legends 1-2 from Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes

  PublisherOA PDFDOI

• Supplementary Materials 1 from Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53

  2023-03-30

  preprintOpen access

  Supplementary Materials 1 from Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53

  PublisherOA PDFDOI

• Data from Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma

  2023-04-03

  preprintOpen access

  <div>Abstract<p>Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. <i>NOTCH1</i> and <i>NOTCH2</i> rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with <i>NOTCH1</i> rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, <i>in vitro</i> and <i>in vivo</i>, whereas cell lines with <i>NOTCH2</i> rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene <i>HES4</i> correlated with outcome in patients with TNBC. Activating <i>NOTCH1</i> point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating <i>NOTCH1</i> mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD–low tumors without <i>NOTCH1</i> mutations were resistant.</p><p><b>Significance:</b><i>NOTCH1</i> mutations, immunohistochemical staining for activated NOTCH1, and <i>HES4</i> expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies. <i>Cancer Discov; 4(10); 1154–67. ©2014 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 1103</p></div>

  PublisherDOI

• The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+ CD8+ effector state, and its deletion improves checkpoint blockade

  Cell Reports · 2023-07-31 · 11 citations

  articleOpen accessCorresponding

  effector state and improves checkpoint inhibitor therapy.

  PublisherOA PDFDOI

• Supplementary Materials 1 from Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53

  2023-03-30

  preprintOpen access

  Supplementary Materials 1 from Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53

  PublisherDOI

Recent grants

• NIH Grant P01CA093615

  NIH · $9.6M · 2013

• NIH Grant R01CA077570

  NIH · $1.2M · 2004

• Notch Regulation of Hematopoietic Cell Fates

  NIH · $7.4M · 2000–2024

• Notch Signaling in Alloimmunity

  NIH · $6.4M · 2011–2027

• Radiobiology and Imaging Program

  NIH · $93.0M · 1997–2027

Frequent coauthors

• Jon C. Aster

  Brigham and Women's Hospital

  257 shared

• Lanwei Xu

  University of Pennsylvania

  244 shared

• Ivan Maillard

  University of Pennsylvania

  177 shared

• Olga Shestova

  University of Pennsylvania

  134 shared

• Stephen C. Blacklow

  Boston VA Research Institute

  113 shared

• David Allman

  University of Pennsylvania

  69 shared

• Juli P. Miller

  DecImmune Therapeutics (United States)

  66 shared

• Yumi Yashiro–Ohtani

  63 shared

Labs

• Pear LabPI