Disorders of erythropoiesis, congenital or acquired
Erythroid differentiation and globin gene regulation; hemopoietic stem/progenitor cell trafficking; homing and mobilization mechanisms; and stem cell function
ORIGINAL RESEARCH CONTRIBUTIONS IN HEMATOPOIESIS/ERYTHROPOIESIS
General: Description of a new form of mild G6PD deficiency in Mediterranean males(Lancet,1964); Characterization of in vivo action of Erythropoietin (JCI,1972); Generation and characterization of 3 new human Erythroleukemia cell lines (Science,1982,Blood,1988,MCB,1988); Generation of monoclonal antibodies against human hematopoietic/erythroid progenitors (Blood 1984,1985); expression of embryonic globins in juvenile myeloid leukemia (Blood,1991); Generation and characterization of anti-human c-kit antibody (Blood,1992).
Studies on human globin regulation and globin switching during development and in adult life: Production of monoclonal anti-human globin antibodies (Lancet,1981,Blood,1983 in collaboration with G.Stamatoyannopoulos); Demonstration that fetal hemoglobin is reactivated in cultures of adult Bone Marrow cells (PNAS,1976,PNAS,1977) or of Peripheral Blood cells (Science,1978); That the reactivation state is related to erythroid cell differentiation/maturation stage (PNAS 1977,1979); Showing the transient reactivation of fetal globin also in vivo in humans post acute erythroid stress (Brit. J. Haem.,1980,Blood,1980); The pharmacologic stimulation of fetal Hb by S-phase compounds (Science,1984,NEJM,1985,Blood,1985,JCI,1988) or by alpha amino butyric acid, or short chain fatty acids (Blood,1988,1989,1995); The creation of heterospecific human/murine erythroid cell hybrids for studying developmental globin switching and activation of fetal globin in adult cells (Cell,1986,Science,1988,Genes and Dev.,1988,PNAS,1991,MCB,1993,1995,Exp. Hem.,2013); Characterization of the globin profile of erythroid cells derived from human ES cells(Blood,2006,Exp. Cell Res.,2008,Stem Cells,2011) or from human iPS cells (Blood,2010).
Role of integrins in Stem/Progenitor cell mobilization and Hematopoiesis regulation: Mobilization of stem/progenitor cells in primates induced by using human anti-VLA antibodies (PNAS,1993) suggesting a role of a4 integrins in Stem/progenitor cell retention in bone marrow; Involvement of alpha4 integrin in homing and self renewal of hematopoietic stem cells(MCB,2003,Blood,2006); creation of several integrin-specific conditional deletion murine models for detailed studies of functional effects (Blood,2006,2008,2009,2011;Exp. Hem.,2007,Stem Cells,2009,Exp. Hem.,2009,Haematologica,2013,Exp. Hem.,2014).
Additional pathways in Stem/Progenitor cell Mobilization: Role of Heparan Sulfated Polysacharides(HSPS) in mobilization and mechanisms (PNAS,2000,Blood,2002); The role of G-protein signaling in mobilization (Blood,2003,2004,Exp. Hem.,2005,Stem Cells Dev.,2014)
Collaborative original studies: Demonstration of the clonal Stem Cell origin in CML (with PJ. Fialkow,1977); characterization of the first beta-Thalassemic patient transplanted in Seattle (with ED. Thomas,1982); cloning of GP1b (H. Lopez,1987); deletion of b-locus LCR in a patient and effects on chromatin structure through the entire b-locus (M. Groudine,1990); correction of beta-S mutation by gene targeting (Homologous Recombination)(O. Smithies,1991); characterization of mES-derived erythroid cells along the primitive and definitive pathways (G. Keller,1993); characterization of Thrombopoietin biologic activity (K. Kaushansky,1994,1995) and first description of a Erythroid/Megakaryocytic bipotent progenitor (K. Kaushansky,1996); targeted expansion of genetically-modified BM cells (through CID)(T. Blau,1998); efficient gene transfer to CD34+ cells using a retargeted Adeno-vector (A. Lieber,2000); transduction of engraftable human cells (in NSG) by foamy vectors (RW. Russell,2002); trisomy correction in Down Syndrome using iPS cells (DW. Russell,2012)
Current Research Interests: Current research efforts are directed : a) At refining the effects of the two erythroid integrins (a4 and a5) early and late in erythroid differentiation by exploiting mouse models with ablation of these integrins, alone and in combination, early and late in erythroid differentiation and b) at using adult Cd34+ cells for gene editing (by different editing platforms) directed at targets in the gamma promoters that can increase fetal Hb or at knocking down silencers of fetal Hb. The efficiency of editing and the transplantability and durability of edited cells is assessed to provide any clinical guidance in selecting the proper targets.
REVIEWS / PERSPECTIVES
Papayannopoulou T: Mechanisms of stem/progenitor cell mobilization: The anti-VLA-4 paradigm. Sem. Hematol. 37 Suppl 2:11-18,2000
Papayannopoulou T: Bone marrow homing: Thwe players,the playfield, and theirevolving roles. Current opinion in Hematol 10(3):214-9,2003
Papayannopoulou T: Current mechanistoic scenarios in hematopoietic stem/progenityor cell mobilization. Blood 103(5):1580-5,2004
Papayannopoulou T, Scadden DT: Stem cell ecology and stem cells in motion. Blood 111(8):3923-30,2008
Bonig H, Papayannopoulou T: Vagrant stem cells draft their gene companions. Cell Stem Cell 7(5):547-8,2010
MigliaccioAr, Whitsett C, Papayannopoulou T, Sadelain M: The potential of stem cells as an in vitro source of red cells for transfusion. Cell Stem Cell 10(2):115-9,2012
Byon JC, Papayannopoulou T: MicroRNAs: Allies or foes in erythropoiesis? J. Cell Physiol. 227(1):7-13,2012
Bonig H, Papayannopoulou T: Hematopoietic stem cell mobilization: updated conceptual renditions. Leukemia 27(1):24-31, 2013