Research Interests

Hematopoietic Regeneration

Research in my laboratory focuses on the role of cell signaling in hematopoietic development and disorders. We study the Notch signaling pathway and its role in regulating the development and cell fate decisions of fetal hematopoietic stem cells (HSC) in mouse models. The overall goal is to understand the molecular and signaling cues that allow for the vast regeneration potential of fetal HSCs and to develop biomedical and bioengineered approaches that will allow adult bone-marrow HSCs to self-renew and expand with the same potency as fetal HSCs.

To accomplish these goals, we rely on transgenic mouse models and embryonic dissection of fetal and adult hematopoietic organs. We use these strategies to accurately detect the hematopoietic development in the mammalian system. Ultimately, through flow

cytometry analysis and FACS, we obtain information from single stem cells for gene expression as well as functional analysis via transplantation to into irradiated recipient mice.

By learning the physiologically relevant signaling events in vivo we aim to create ex vivo microenvironments that allow for expansion and self-renewal of stem cells for clinical and therapeutic applications.

T-cell Leukemia

Notch signaling is essential for development of multiple tissues and organs including blood cells. T-cells require robust Notch signaling during thymic development, however when gain-of-function Notch mutants are expressed in developing T-cells, elevated signaling levels drive onset of T-cell Acute Lymphoblastic Leukemia (T-ALL) in many pediatric patients. We are investigating genetic (CRISPR/Cas9 gene editing) and molecular (small molecule and gene target screening) approaches to specifically target leukemic Notch signaling in T-cells and maintain normal Notch signaling in other tissues.

1. Gerhardt DM*, Pajcini KV*, D’altri T, Tu L, Jain R, Xu L, Chen MJ, Rentschler S, Shestova O, Wertheim GB, Tobias JW, Kluk M, Wood AW, Aster JC, Gimotty PA, Epstein JA, Speck N, Bigas A, Pear WS. 2014. Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes Dev. Mar 15;28(6):576-93. PMCID:PMC 3967047 (*Authors contributed equally to this work)
2. Shao L, Sottoriva K, Palasiewicz K, Hyun JS, Soni SS, Gao X, Cuervo H, Malik AB, Rehman J, Pajcini KV. A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche. Haematologica. November 2019 104: 2164-2177; doi:10.3324/haematol.2018.208660. PMID: 30923091
3. Shao L*, Elujoba-Bridenstine A*, ZinkKE, SanchezLM, CoxBJ, PollokKE, Sinn A, Bailey BJ, Sims E, Cooper S, Broxmeyer HE, Pajcini KV,˚ Tamplin OJ˚. The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells. Blood. 2020 Sep 3: blood. 2019004415. doi: 10.1182/blood.2019004415. PMID: 32881992. (*Authors contributed equally to this work), (˚Co-corresponding authors)
4. Shao L, Paik NY, Sanborn MA, Bandara T, Vijaykumar A, Sottoriva K, Rehman J, Nombela-Arrieta C, Pajcini KV. Hematopoietic Jagged1 is a fetal liver niche factor required for functional maturation and engraftment of fetal hematopoietic stem cells. PNAS May 2023, 120 (20) e2210058120. PMID: 37155858
5. Toboz P, Amiri M, Tabatabaei N, Dufour CR, Kim SH, Fillebeen C, Ayemoba CE, Khoutorsky A, Nairz M, Shao L, Pajcini KV, Kim KW, Giguère V, Oliveira RL, Constante M, Santos MM, Morales CR, Pantopoulos K, Sonenberg N, Pinho S, Tahmasebi S. The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages. PNAS. 2022 30;119(35):e2121251119. doi: 10.1073/pnas.2121251119. Epub 2022 Aug 22. PMID: 35994670
6. Sargis T, Youn SW, Thakkar K, Naiche LA, Paik NY, Pajcini KV, Kitajewski JK. Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties. Angiogenesis 2022 Nov 15.doi: 10.1007/s10456-022-09861-6. PMID:36376768
7. Paik NY, Neethling JC, Anwar M, Gupta P, Sanborn MA, Shen Z, Bandara T, Kitajewski JK, Rehman J, Shin JW, Mehta D, Pajcini KV. Notch transcriptional target Tmtc1 maintains vascular homeostasis. Mol. Life Sci. 81, 370 2024 Aug. doi.org/10.1007/s00018-024-05407-9
8. Pajcini KV*, Xu L, Shao L, Petrovic J, Palasiewicz K et al. MafB is a novel enhancer of oncogenic Notch signaling in T-cell acute lymphoblastic leukemia. Science Signaling. 2017 Nov 14;10(505). pii: eaam6846. doi: 10.1126/scisignal.aam6846. PMID:29138297(*Co-corresponding author)
9. Sottoriva K, Paik NY, White Z, Bandara T, Shao L, Sano T, Pajcini KV. Notch-IL21 signaling axis promotes bone marrow T cell progenitor expansion. JCI Insight March 2022.;7(9):e157015. https://doi.org/10.1172/jci.insight.157015. PMID: 35349492

B.S., University of Pittsburg, PA; Microbiology (2004).
PhD, Stanford University; Microbiology and Immunology (2009).
Postdoc, University of Pennsylvania; Cell Signaling (2015).

2008- present                    International Society of Stem Cell Research

2014- present                    American Society of Hematology

2017- present                    International Society of Experimental Hematology

2024                                    Invited speaker for GRC Notch Signaling in Development, Regeneration & Disease.(Bates College, Maine)

2023                                    Selected speaker for 52^nd Annual ISEH Scientific Meeting (New York, NY)

2022                                    Selected speaker for 64^rd Annual ASH Conference (New Orleans, Louisiana)

2022                                    Selected speaker for GRC Notch Signaling in Development, Regeneration & Disease.(Bates College, Maine)

2021                                    Selected speaker for 63^rd Annual ASH Conference (Atlanta, Georgia)

2020                                    Selected speaker for 19^th Annual ISSCR Conference (Virtual Presentation, June 2020)

2020                                    Invited Speaker, Children’s Hospital of Philadelphia (CHOP) Hematology-Oncology Seminar Series (Philadelphia, Pennsylvania)

Research in our laboratory focuses on the role of cell signaling in hematopoietic development and disorders. Specifically, the Notch signaling pathway regulates development of fetal hematopoietic stem cells and stem cell fate decisions in mouse models. The overall goal is to understand the molecular and signaling cues that allow for the vast regeneration potential of fetal HSCs and to develop biomedical and bioengineered approaches that will allow adult bone-marrow HSCs to self-renew and expand with the same potency as fetal HSCs. To accomplish these goals, we rely on transgenic mouse models and embryonic dissection of fetal and adult hematopoietic organs. We use these strategies to accurately detect the hematopoietic development in the mammalian system.