Kostandin Pajcini

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.

Shao L, Elujoba-Bridenstine A, Zink KE, Sanchez LM, Cox BJ, Pollok KE, Sinn AL, Bailey BJ, Sims EC, Cooper SH, Broxmeyer HE, Pajcini KV, Tamplin OJ*. The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells. Blood. 137:775-787, 2021. PMCID: PMC7885825 (available on 2022-02-11). *Co-corresponding authors

Shao L, Sottoriva K, Palasiewicz K, Zhang J, Hyun J, Soni SS, Paik NY, Gao X, Cuervo H, Malik AB, Rehman J, Lucas D, Pajcini KV. A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche. Haematologica. doi: 10.3324/haematol.2018.208660 [Epub ahead of print], 2019.

Pajcini KV, Xu L, Shao L, Petrovic J, Palasiewicz K, Ohtani Y, Bailis W, Lee C, Wertheim GB, Mani R, Muthusamy N, Li Y, Meijerink JPP, Blacklow SC, Faryabi RB, Cherry S, Pear WS. MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia. Sci Signal. 10, 2017.

Gerhardt DM, Pajcini KV, D'altri T, Tu L, Jain R, Xu L, Chen M, Rentschler S, Shestova O, Wertheim G, Aster JC, Gimotty PA, Speck NA, Bigas A, Pear WS. The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes and Development. 28: 576-593, 2014.

Pajcini KV, Corbel SY, Pomerantz JH, Sage J, Blau HM. Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. Cell Stem Cell. 7:198-213, 2010.