Research Abstract
My basic biology laboratory has been pivotal in the elucidation of the cellular and molecular mechanisms of hematopoietic cells through the Rho family of GTPases in health and disease. We provided the basis for understanding of the physiological cell-autonomous and microenvironment/cytokine signaling and metabolic/mitochondrial dependent mechanisms in the context of myeloid progenitor migration and bone marrow retention (Gu Y et al., Science 2003; Cancelas JA et al., Nat. Med., 2005; Sengupta A et al., PNAS 2011; Gonzalez-Nieto D et al., Blood 2012; Taniguchi-Ishikawa et al., PNAS 2012; Taniguchi-Ishikawa et al., Nature Comm. 2013; Chang KH et al, Cell Reports, 2014; Chang KH et al., Nature Commun., 2015; Althoff MJ et al., Blood 2020; Golan K et al., Blood 2020).
Our group also defined the mechanisms that control oncogenic tyrosine kinase signals dependent transformation in leukemic progenitors and identifying specific intrinsic and microenvironment-dependent signaling through Rho GTPases (Yamada Y et al., Blood 2006; Thomas EK et al., Cancer Cell 2007; Yamada Y et al., Blood 2008; Sengupta A et al., Blood 2010; Sengupta A et al., Blood 2012; Chang KH et al., Blood 2012; Kesarwani M et al., Nat. Med., 2017; Nayak RC et al., Nat. Comm., 2018; Hegde S et al., Leukemia 2021; Nayak RC et al., Nat. Comm., 2022).
Through hematopoietic differentiation of human induced pluripotent stem cells (iPSC) from SCN patients, our laboratory has unveiled the pathogenetic mechanisms of neutropenia in patients with ELANE mutations resulting in neutrophil elastase intracellular mislocalization, endoplasmic reticulum stress and apoptosis along with a non-cell autonomous effect on myeloid progenitors responsible to a bias towards monocytosis (Tidwell T et al., Blood 2014; Nayak RC et al., JCI 2015). Our laboratory has also developed specific methods for the characterization of iPSC from the progenitor cell biology consortium (Salomonis N et al., Stem Cell Rep., 2016; Daily K et al., Scientific Data, 2017) and developed/validated new methods for cryopreservation/delivery of functionally active lymphocyte populations in the context of adoptive transplantation (Worsham D et al., Transfusion 2017).
My translational group has optimized methods of progenitor (Cancelas JA et al., Transfusion 2016) and granulocyte transfusion in neutropenic patients (Cancelas JA et al., Transfusion 2014) and validated novel methods to preserve and store platelets, red cells and T cells in clinical multi-center trials (Cancelas JA et al., Transfusion 2022; Hegde S et al., Transfusion 2021; Slichter S et al., Transfusion 2018; Worsham DN et al., Transfusion 2017; Dumont LJ, Cancelas JA, et al. Transfusion. 2014; Cancelas JA et al., Transfusion. 2014; Dumont LJ, Cancelas JA, et al. Transfusion. 2013; Dumont LJ, Cancelas JA, et al. Transfusion. 2013; Cancelas JA, et al. Transfusion. 2011; Cancelas JA, et al. Transfusion. 2011; Cancelas JA, et al. Transfusion. 2011; Bandarenko N, Cancelas JA et al. Transfusion. 2007; AuBuchon JP, Cancelas JA, et al. Transfusion. 2006). Our group is now actively searching for the mechanisms that control cold platelet damage and identified key molecular signals and methods to prevent cold storage damage (Hegde S et al., Transfusion 2021; Hegde S et al., in preparation) and lyophilized platelets (Ohanian M, Cancelas JA et al., Am. J. Hematol., 2021). Our group has generated first-in-human clinical data for a variety of biological therapies (Cancelas JA et al., Transfusion 2021; Ohanian M, Cancelas JA et al., Am. J. Hematology, 2021; D’Alessandro A et al., Transfusion 2020; Slichter S et al., Transfusion 2018; Cancelas JA et al., Transfusion 2017; Cancelas JA et al., Transfusion 2015; Dumont, Cancelas et al., Transfusion 2013).
