Ricerca >> Laboratory of Molecular Haematopoiesis and Stem Cell Biology
 

Laboratory of Molecular Haematopoiesis and Stem Cell Biology

UMG Campus – Biosciences Building, Level 7 -  Tel: 0961 369-4056 - Fax: 0961 369-4090

 

MEMBERS OF THE LABORATORY
Name Position Tel. e-mail
Giovanni MORRONE Professor of Biochemistry +39 0961 369-4072 morrone@unicz.it
Heather M. BOND Lecturer of Biochemistry +39 0961 369-4081 bond@unicz.it
Maria MESURACA Lecturer of Biochemistry +39 0961 369-4081 mes@unicz.it
Marco GIORDANO Post-doctoral fellow +39 0961 369-4056 m_giordano3456@yahoo.it
Francesca BERNAUDO PhD student +39 0961 369-4056 francebern@libero.it
Emanuela CHIARELLA PhD student +39 0961 369-4056 emanuelachiarella@libero.it
Bruna CODISPOTI PhD student +39 0961 369-4056 brunacodispoti@alice.it
Giovanna NAPPO PhD student +39 0961 369-4056 giovanna.nappo@yahoo.it
Stefania SCICCHITANO PhD student +39 0961 369-4056 ste.scicchitano@gmail.com
Annamaria ALOISIO Junior fellow +39 0961 369-4056 aloisioannamaria@tiscali.it
Teresa GRILLONE Junior fellow +39 0961 369-4056 teresa.grillone@alice.it
Maria Grazia MARAFIOTI Junior fellow +39 0961 369-4056 mariagrazia.marafioti@gmail.com
Cristina B. SPOLETI Junior fellow +39 0961 369-4056 cristinaspoleti@gmail.com


KEYWORDS
Haematopoiesis - Stem Cells - Cancer, Leukaemia - Gene Expression - Gene transfer

RESEARCH
Our research is focused on the study of the molecular mechanisms that govern the homeostasis of the immature cell compartment of diverse tissues, with particular regard to the haematopoietic system, and of the dysregulation of these mechanisms that lead to the development of malignancies.


Experimental models of myeloid leukaemogenesis
In collaboration with other research groups in Italy, Europe and U.S.A. we have contributed to the development of experimental models of myeloid leukaemogenesis based on the retro- or lentiviral mediated transfer of leukaemia-associated oncogenes into human CD34+ cells. Using this system, we have shown that enforced expression of diverse candidate oncogenes and/or of constitutively active signal transduction factors profoundly alters the self-renewal, proliferation and differentiation potential of normal haematopoietic stem and progenitor cells, and in some cases can result in the development of a frankly leukaemic phenotype. We are currently investigating the role of functional interactions among these molecules, as well as of their possible cooperation with microRNAs and/or other regulatory factors, in the pathogenesis of acute myeloid leukaemias.
 
ZNF521: a novel regulator of normal and malignant stem and progenitor cells
In previous studies, we have identified a set of genes highly expressed in primitive haematopoietic progenitors but not in mature leukocytes. One of these encodes a protein with 30 zinc finger motifs that displays the features of a multi-functional transcription co-factor, and has been designated zinc finger protein 521 (EHZF/ZNF521). ZNF521 is a potent inhibitor of EBF1, a transcription factor essential for the specification of the B-lymphoid lineage, that has also implicated in the control of neurogenesis, osteogenesis and adipogenesis.

We have characterised the molecular interaction between these two factors, identified the zinc fingers motifs that are required for this interaction and for the inhibition of the transcriptional activity of EBF1 by ZNF521, and demonstrated that silencing of ZNF521 in early haematopoietic progenitors strongly enhanced B-cell development. Our more recent studies show that relatively high expression of ZNF521 is present in most acute myeloid leukaemias, in particular in those bearing aberrations of the MLL genes, where ZNF521 expression appears to be required for the leukaemic phenotype.
In addition to haematopoiesis, ZNF521 is an important regulator of neurogenesis. We have studied its role in medulloblastoma, the most frequent malignant brain cancer of childhood, as ZNF521 is highly expressed in cerebellar granule neuron precursors that are considered the cells-of-origin of a substantial fraction of these tumours. We have shown that ZNF521 stimulates the self-renewal, migration and tumourigenicity of immature medulloblastoma cells. These activities required the interaction of ZNF521 with the nucleosome remodeling and histone deacetylase (NuRD) complex through a 12-amino acid motif located at the N-terminal end of the ZNF521 protein. This investigation is being extended to glioma-initiating cells. We are also attempting to define the complete repertoire of molecular partners and downstream target of ZNF521 in haematopoietic and neural cells to gain a better understanding of its mechanism of action.

New lentiviral vectors for gene transfer in haematopoietic cells
Lentiviruses are widely used gene transfer vectors and they are particularly useful to transduce haematopoietic stem cells because of their efficiency in infecting quiescent cells. We have designed, constructed and validated novel dual-promoter lentiviral vectors where the transgene expression is directed by the potent UbiC promoter, and the expression of the reporter fluorescent protein, EGFP, is driven by a short fragment of the regulatory region of the Wisckott-Aldrich gene isolated and characterised in our laboratory (Petrella et al., Blood 1998). These vectors proved highly efficient in transducing haematopoietic cells, including the most primitive progenitors and induced abundant and persistent expression of both transgene and fluorescent reporter protein in these cells, and therefore represent valuable tools to study the properties of genes implicated in the control of normal and malignant haematopoiesis.


	
RECENT PUBLICATIONS
  • Zhang Y, Morrone G, Zhang J, Chen X, Lu X., Ma L, Moore MAS, Zhou P (2003) Regulation of HOX homeodomain proteins by ubiquitin-dependent proteolysis. EMBO J. 22:6057-6067
  • Bond HM°, Mesuraca M°, Carbone E, Bonelli P, Agosti V, Amodio N, De Rosa G, Di Nicola M, Gianni MA, Moore MAS, Hata A, Grieco M, Morrone G*, Venuta S* (2004) Early Hematopoietic Zinc Finger protein (EHZF), the human homolog to Evi3, is highly expressed in primitive human hematopoietic  cells. Blood 103: 2062-2070     
  • Ye Q, Shieh J-H, Morrone G, Moore MAS. (2004) Expression of activated Notch-4 (Int-3) modulates the proliferation and promotes expansion of hematopoietic progenitors. Leukemia, 18:777-787.   
  • Schuringa JJ, Chung K-Y, Morrone G, Moore MAS  (2004) Constitutive activation of STAT5A promotes human hematopoietic stem cell self-renewal and erythroid differentiation. J. Exp. Med., 200: 623-635
  • Schuringa JJ, Wu K, Morrone G, Moore MAS  (2004) Enforced activation of STAT5A facilitates the generation of ES-derived hematopoietic stem cells that contribute to hematopoiesis in vivo. Stem Cells 22:1191-1204
  • Chung K-Y, Morrone G, Schuringa JJ, Wong B, Dorn D, Moore MAS  (2005) Enforced expression of Flt3 ITD in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis Blood 105:77-84 
  • Carbone E, Neri P, Mesuraca M, Fulciniti MT, Otsuki T, Pende D, Groh V, Spies T, Pollio G, Cosman D, Catalano L, Tassone P, Rotoli B, Venuta S. (2005) HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood 105:251-258
  • Chung K-Y, Morrone G, Schuringa JJ, Plasilova M., Shieh J-H, Zhang Y, Zhou P, Moore MA (2006) Enforced expression of NUP98-HOXA9 in human CD34+ cells provides a proliferative advantage and enhances stem cell self-renewal. Cancer Res. 66:11781-11791
  • Moore MAS, Dorn D, Schuringa JJ, Chung K-Y, Morrone G (2007) Constitutive activation of Flt3 and STAT5A enhances self-renewal and alters differentiation in normal and leukemic stem cells Exper. Hematol. 35:105-116
  • Moore MAS, Chung K-Y, Dorn D, Plasilova M., Schuringa JJ, Shieh J-H, Zhou P, Morrone G (2007) NUP98 dysregulation in myeloid leukemogenesis Ann NY Acad Sci. 1106:114-142
  • Bond HM, Mesuraca M, Amodio N, Mega T, Pelaggi D, Agosti V, Fanello D, Bullinger L, Grieco M, Moore MAS, Venuta S, Morrone G (2008) Early hematopoietic zinc finger protein/zinc finger protein 521 (EHZF/ZNF521): a candidate regulator of diverse immature cells. Int. J. Biochem. Cell Biol. 40:848-854
  • La Rocca R, Fulciniti M, Lakshmikanth T, Mesuraca M, Hassan TA, Mazzei V, Amodio N, Catalano L, Rotoli B, Ouerfelli O,  Grieco M, Gulletta E, Bond HM, Morrone G, Ferrone S, Carbone E (2009) Early hematopoietic zinc finger protein (EHZF/ZNF521) prevents tumor cell recognition by natural killer cells. J. Immunol., 182:4529-4537.
  • Leuci V, Gammaitoni L, Capellero S, Sangiolo D, Mesuraca M, Bond HM, Migliardi G, Cammarata C, Aglietta M, Morrone G*, Piacibello W* (2009) Efficient transcriptional targeting of human CD34+ cells and all blood cell lineages by a lentiviral vector containing the regulatory element of the WASP gene. Stem Cells 27:2815-2823.
  • Mega T, Lupia M, Amodio N, Horton SJ, Mesuraca M, Pelaggi D, Agosti V, Grieco M, Chiarella E, Spina R, Moore MAS, Schuringa JJ, Bond HM*, Morrone G* (2011) Zinc finger protein 521 antagonizes early B-cell factor 1 and modulates the B-lymphoid differentiation of primary hematopoietic progenitors. Cell Cycle, 10:2129-2139.
  • Horton SJ, Jaques J, Woolthuis C, Huls G, Mesuraca M, Morrone G, Vellenga E, Schuringa JJ (2013) Modeling the origins of MLL-AF9 leukemias: the transformation potential of human hematopoietic cells along different lineages changes during ontogeny. Leukemia, 27:1116-1126.
  • van den Boom V, Rozeveld-Geugien M, Bonardi F, Malanga D, van Gosliga D, Heijink AM, Viglietto G, Morrone G, Fusetti F, Vellenga E, Schuringa JJ (2013) Non-redundant and locus-specific gene repression functions of PRC1 paralog family members in human hematopoietic stem/progenitor cells. Blood 121:2452-2461
  • Lee J, Shieh J-H, Zhang J, Liu L, Eom JY, Morrone G, Moore MAS, Zhou P (2013) Improved ex vivo expansion of adult hematopoietic stem cells by overcoming CUL4-mediated degradation of HOXB4. Blood, 121(20):4082-4089.
  • Osaki H, Walf-Vorderwülbecke V, Mangolini M, Zhao L, Horton SJ, Morrone G, Schuringa JJ, De Boer J, Williams O (2013) The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis Leukemia, 27:1461-1468.
  • Spina R°, Filocamo G°, Iaccino E, Scicchitano S, Lupia M, Chiarella E, Mega T, Bernaudo F, Pelaggi D, Mesuraca M, Pazzaglia S, Bar EE, Bond HM, Eberhart CG*, Steinkuhler C*, Morrone G* (2013) Critical role of zinc finger protein 521 in the control of growth and tumourigenicity of human medulloblastoma cells. Oncotarget 4:1280-1292.
  • Misaggi R, Di Sanzio M, Cosentino C, Bond HM, Scumaci D, Romeo F, Stellato C, Giurato G, Weisz A, Quaresima B, Barni T, Amato F, Viglietto G, Morrone G, Cuda G, Faniello MC, Costanzo FS (2014) Identification of H ferritin-dependent and independent genes in K562 differentiating cells by targeted gene silencing and expression profiling. Gene 535:327-335.
  • Massimino M, Consoli ML, Mesuraca M, Stagno F, Tirrò E, Stella S, Pennisi MS, Romano C, Buffa P, Bond HM, Morrone G, Sciacca L, Di Raimondo F, Manzella L, Vigneri P (2014) IRF5 is a target of BCR-ABL kinase activity and  reduces CML proliferation. Carcinogenesis, (in press).
  • Bond HM, Mesuraca M, Morrone G (2014) Targeting Leukemia stem cells: in vitro veritas? Oncotarget, (in press).
  • Chiarella E, Carrà G, Scicchitano S, Codispoti, B, Mega T, Lupia M, Pelaggi D, Marafioti MG, Aloisio AM, Giordano, M, Nappo G, Spoleti CB, Grillone T, Giovannone ED, Spina R, Bernaudo F, Moore MAS, Bond HM, Mesuraca M*, Morrone G* UMG Lenti: novel lentiviral vectors for efficient transgene- and reporter gene expression in human hematopoietic progenitors. (submitted for publication)
  • Mesuraca M°, Chiarella E°, Codispoti B, Lupia M, Horton SJ, Scicchitano S, Döhner H, Schuringa JJ, Bond HM, Bullinger L*, Morrone G* Abundant expression of zinc finger protein 521 in AMLs correlates with specific genetic aberrations and contributes to the leukaemic phenotype in AMLs with MLL rearrangements. (in preparation).
 
PRINCIPAL COLLABORATIONS
 
Università di Torino
Giuseppe Saglio
University of Groningen Medical Center (NL)
Jan-Jacob Schuringa
Università di Catania
Paolo Vigneri
Memorial Sloan-Kettering Cancer Center (USA)
Malcolm A.S. Moore
IRRCS S. Giovanni Rotondo
Angelo Vescovi
Cornell University Weill Medical Center (USA)
Pengbo Zhou
Institute of Child Health, London (UK)
Owen Williams
Jons Hopkins University Medical School (USA)
Charles G. Eberhart
University of Ulm (DE)
C. Beltinger, Lars Bullinger
Harvard University Medical Center (USA)
L.D. Notarangelo, R. Baron
University of Freiburg i.Br. (DE)
Michael Lübbert, Marie Follo
U. of Louisville, JG Brown Cancer Center (USA)
Levy J. Beverly
  German Cancer Research Centre (DKFZ) (DE)
Violaine Goidts, Marcel Kool, Stefan Pfister

L’Ateneo Magna Graecia di Catanzaro è stato fra i primi in Italia ad adottare il nuovo modello organizzativo dettato dalla legge 30 Dicembre 2010 n. 240, che prevede una profonda rimodulazione dell’intero sistema universitario incentrata, fra l’altro, proprio sul ruolo dei Dipartimenti, ai quali sono attribuiti i compiti di organizzazione della ricerca scientifica e delle attività didattiche e formative. Il Dipartimento di Medicina Sperimentale e Clinica nasce il 28 Settembre del 2011 dalla volontà di 50 ricercatori appartenenti ad aree scientifico-disciplinari apparentemente lontane di mettere insieme le loro risorse  e competenze scientifiche per sviluppare una comune attività di ricerca di base, clinica e traslazionale volta allo studio epidemiologico, fisiopatologico, diagnostico e terapeutico della patologia oncologica, dismetabolica e vascolare.
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