Rossella Manfredini
Rossella Manfredini
e-mail:
website: www.dsb.unimo.it/
affiliation: Università di Modena-Reggio Emilia
research area(s): Stem Cells And Regenerative Medicine, Genetics And Genomics
Course: Molecular and Regenerative Medicine
University/Istitution: Università di Modena-Reggio Emilia
Date and place of birth: November 2, 1962, Modena, Italy.
Education: 1988. Biological Sciences Degree with honors, University of Modena, Italy
Postgraduate training:1994: PhD in Experimental Hematology, University of Modena, School of Medicine, Modena, Italy (thesis: "Role of c-myb and fes protooncogenes in myeloid differentiation and leukemogenesis").
1996: Postgraduate School of Biochemistry and Clinical Chemistry, University of Modena, School of Medicine, Modena, Italy.(thesis: " Study of the role of fes, Grb2 and SOS in signal transducion mechanisms during myeloid differentiation").
Fellowships: 1989: AIRC (Italian Association for Cancer Research) "Study of the mechanisms of gene expression regulation in leukemic blast cells". 1994: Italian League against cancer: "Study of apoptosis-involved genes in tumor cells". 1995: Italian League against cancer: "Study of molecular basis of differentiation block in acute leukemic blast cells".
Post doctoral training: 6/1989-12/1989: Laboratory of Prof. Renato Baserga, Temple University, Philadelphia, USA, in the field of the genetic control of the cell cycle.
Honors and Awards:1988-1989: "MEDICINA" "1988" and "1989" Award of The Italian Medical Encyclopedia. 1992: Lega Milanese Lotta contro i Tumori" Award. 1994: Società Italiana di Cinetica Cellulare Applicata e di Base (SICCAB) Award.
Patents: 1998: International USA Patent N. 08/859.389 "Use of c-Fes specific antisense oligonucleotides and ATRA in M3 type leukemias".
Academic Career: 1996-2002: Researcher in Applied Biology, University of Modena. 2002-today: Associate Professor in Applied Biology, University of Modena & Reggio Emilia.
In July 2010, she resulted as eligible in a comparative evaluation for a Full Professor position (BIO/13). In September 9th, she was convened in this role by the Faculty of Biosciences and Biotechnology, University of Modena and Reggio Emilia.
Book writing: She participated in the book writing of “Biology” (Ed. Piccin, Nuova Libraria S.p.A., 2008), as a author of the chapter “Stem cells”.

Research Activity: 1988-today. Hemopoietic Stem Cells Laboratory, Center for Regenerative , Department of Biological Sciences,University of Modena & Reggio Emilia, Modena, Italy.
The research activity of Prof. Rossella Manfredini is documented by 65 publications in extenso and 190 meeting abstracts.
Research Topics:
1. Gene expression regulation in normal and leukemic differentiation.
2. Role of c-myb, c-fes, and bax protooncogenes in myeloid proliferation, differentiation and apoptosis.
3. Gene expression profiling by DNA microarrays of hematopoietic stem cells, myeloid precursors and differentiated cells.
4. Functional role of CD34 antigen in human myelopoiesis.
5. Gene expression profiling by DNA microarrays of Leukemic Stem Cells (LSC) of myeloproliferative diseases (Chronic Myeloid Leukemia, Idiopatic Myelofibrosis and Essential Thrombocytemia)
1- Tagliafico E, Tenedini E, Manfredini R, Grande A, Ferrari F, Roncaglia E, Bicciato S, Zini R, Salati S, Bianchi E, Gemelli C, Montanari M, Vignudelli T, Zanocco-Marani T, Parenti S, Paolucci P, Martinelli G, Piccaluga PP, Baccarani M, Specchia G, Torelli U, Ferrari S. Identification of a molecular signature predictive of sensitivity to differentiation induction in acute myeloid leukemia. Leukemia. 2006 Oct;20(10):1751-8. IF 8.296
2- Guglielmelli P, Zini R, Bogani C, Salati S, Pancrazzi A, Bianchi E, Mannelli F, Ferrari S, Le Bousse-Kerdiles MC, Bosi A, Barosi G, Migliaccio AR, Manfredini R*, Vannucchi AM*. Molecular Profiling of CD34+ Cells in Idiopathic Myelofibrosis Identifies a Set of Disease-Associated Genes and Reveals the Clinical Significance of Wilms' Tumor Gene 1 (WT1). Stem Cells. 2007 Jan;25(1):165-73. *R.Manfredini and A.M.Vannucchi share the senior authorship. IF 7.749

3- Rossi L, Manfredini R, Bertolini F, Ferrari D, Fogli M, Zini R, Salati S, Salvestrini V, Gulinelli S, Adinolfi E, Ferrari S, Di Virgilio F, Baccarani M, Lemoli RM. The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration. Blood. 2007 Jan 15;109(2):533-42. IF 10.555

4- Rutella S, Bonanno G, Procoli A, Mariotti A, de Ritis DG, Curti A, Danese S, Pessina G, Pandolfi S, Natoni F, Di Febo A, Scambia G, Manfredini R, Salati S, Ferrari S, Pierelli L, Leone G, Lemoli RM. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features. Blood. 2006 Jul 1;108(1):218-27. IF 10.555

5- Magnoni C., Tenedini E., Benassi L., Bernardi C., Gualdi G., Ferrari F., Manfredini R., Bicciato S., Ferrari Se., Giannetti A., Tagliafico E. Transcriptional profiles in melanocytes from unaffected skin distinguish the neoplastic growth pattern in patients with melanoma. Br J Dermatol. 2007 Jan;156(1):62-71. IF 4.26

6- Salati S., Bianchi E., Zini R., Tenedini E., Quaglino D., Manfredini R*. and Ferrari Se. “Eosinophils, but not neutrophils, exhibit an efficient DNA repair machinery and high nucleolar activity”. Haematologica, 92(10): 1311-18, 2007. IF 6.416

7- Guglielmelli P., Tozzi L., Pancrazzi A., Bogani C., Antonioli E., Ponziani V., Poli G., Zini R., Ferrari Se., Manfredini R., Bosi A. and Vannucchi A.M.. “MicroRNA expression profile in granulocytes from primary myelofibrosis patients”. Experimental hematology, 35(11):1708, 2007. IF 3.106

8- Conigliaro A, Colletti M, Cicchini C, Guerra MT, Manfredini R, Zini R, Bordoni, V, Siepi F, Leopizzi M, Tripodi M, Amicone L. Isolation and characterization of a murine resident liver stem cell. Cell Death Differ. Cell Death Differ. 2008 Jan;15(1):123-33. Epub 2007 Oct 12. IF 8.24

9- Salati S., Zini R., Bianchi E., Testa A., Mavilio F., Manfredini R.* and Ferrari Se. “Role of CD34 Antigen in Myeloid Differentiation of Human Hematopoietic Progenitor Cells”. Stem Cells, 2008, Apr;26(4):950-9. *Corresponding Author. IF 7.747

10- L Catani, R Zini, D Sollazzo, E Ottaviani, AM Vannucchi, S Ferrari, M Baccaran, N Vianelli, RM Lemoli and R Manfredini. Molecular profile of CD34+ stem/progenitor cells according to JAK2V617F mutation status in essential thrombocythemia. Leukemia, 2009, Jan 8. Epub ahead of print. IF 8.296

11- C Cellai, A Laurenzana, E Bianchi, S Sdelcia, R Manfredini, A M. Vannucchi, R Caporale, M Balliu, F Mannelli, Se Ferrari, A Bosi, D Miniati, P L. Cocco, S Veronneau, J Stankova, and F Paoletti. Mechanistic insight into WEB-2170-induced apoptosisin human acute myelogenous leukemia cells: The crucial role of PTEN. Exp Hematol. 2009 Oct;37(10):1176-1185.e21. IF 3.106

12- RM. Lemoli, M Fogli, E. Bianchi, V. Salvestrini, S.Salati, M. Amabile, F. Bertolini, A. Tafuri, R. Zini, N. Testoni, C. Rabascio, L. Rossi,G. Martinelli, M. Baccarani, S. Ferrari and R. Manfredini. Molecular and functional analysis of stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34 negative cell population with intrinsic resistance to imatinib treatment. Blood. 2009 Dec 10;114(25):5191-200. Epub. IF 10.555

13- E. Bianchi, R. Zini, S. Salati, E. Tagliafico, R. Manfredini and Se. Ferrari. "c-Myb supports erythropoiesis through transactivation of KLF1 and LMO2 expression ". Blood. 2010 Nov 25; 116(22):e99-110. Epub 2010 Aug 4. IF 10.555

14- Xynos A., Corbella P., Belmonte N., Zini R., Manfredini R., and Ferrari G. “Bone marrow-derived hematopoietic cells undergo myogenic differentiation following a Pax-7 independent pathway”. Stem Cells, 2010 May;28(5):965-73. IF 7.747

15- Ferrari D., Gulinelli S., Salvestrini V., Lucchetti G., Zini R., Manfredini R., Rossi L., Idzko M., Ferrari S., Di Virgilio F., and Lemoli R.M. “Purinergic signaling modulates human bone marrow-derived mesenchymal stem cells function”. Exp Hematol, in press. IF 3.106
Project Title:
Molecular and functional characterization of Hemopoietic Stem Cells from Myeloproliferative neoplasms
Myeloproliferative neoplasms (MPNs) are molecularly and clinically heterogeneous hematological neoplasia that include three clinical entities, namely polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Despite being quite common disorders, there is still no effective therapy to prevent the complications associated with their course and the evolution to acute leukemia nor to prolong survival in the most clinically challenging and more rapidly fatal PMF. These therapeutic gaps are largely due to the fact that only recently recurrent molecular abnormalities have been appreciated, ie the JAK2V617F and MPLW515 mutations. However, notwithstanding these recent breaking-through discoveries, available information do not suffice to explain entirely the molecular pathogenesis of MPNs, thus slowing development of effective and hopefully curative treatments. Thus, there are urgent scientific and clinical needs that call for being met in order to improve clinical management and design innovative therapies for MPN patients.
The topics of investigation we have identified as worthwhile of current investigation are represented by the search of novel somatic mutations and the elucidation of abnormalities in other key genetic checkpoints, ie epigenetic and microRNA-dependent gene expression regulation, that are associated with the origin, phenotypic determination, and clonal evolution of the disorders and might serve as diagnostic or prognostic biomarkers. To reach these objectives we have designed an advanced molecular approach that by exploiting both the immediate availability of large collection of MPN patient series and biological samples and its prospective implementation by the team, is intended to build up an integrative genetic, epigenetic, coding RNAs and microRNA portrait of the hematopoietic progenitors. All these information will have immediate application for improving and/or designing disease classification systems and for exploiting and elucidating the mechanism of action of novel drugs.


Project Title:
Molecular analysis of Leukemia Stem Cells in Chronic Myelogenous Leukemia
Background: Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder that originates at the level of Hematopoietic Stem Cell (HSC) as a consequence of the t(9;22) translocation, giving rise to the Ph (Philadelphia) Chromosome and to the BCR-ABL oncoprotein. Currently, the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) is considered the standard therapy in CML. Despite the great success of this targeted therapy, the exposure to imatinib may not completely eliminate leukemic progenitors. The stem cells concept suggests that leukemic stem cells are intrinsically refractory to imatinib treatment and therefore they are responsible for minimal residual disease (MRD) and relapse. It is therefore important to gain further insight on the molecular and functional properties of the stem cell compartment in CML, in view of the development of more effective therapies. Up to date, a number of gene expression studies have been performed to identify the molecular signature of CML cells, however, no global molecular and functional analysis of the CML stem cell compartment have been reported. Moreover, in the last few years, many studies linked the microRNAs (miRNAs) to hematopoiesis regulation, suggesting also a possible role for miRNAs in leukemogenesis. So far, informations about the implication of miRNAs in CML pathogenesis are very limited. Understanding whether and how miRNAs could play a role in CML pathogenesis could lead to the design of new targeted therapies capable of eliminating the leukemic stem cell compartment.
Objectives: The main objectives of this project are:
1. Identification of miRNAs deregulated in CML LSCs.
2. Characterization of the role played by these miRNAs and by their targets in CML pathogenesis and disease progression.
3. Identification of regulatory mechanisms responsible for miRNAs aberrant expression in CML.
Experimental design: In order to gain further insights into the role played by miRNAs in the genesis of CML, we intend to compare miRNAs expression in CML LSCs and normal HSCs. Integrative analysis of miRNA and mRNA expression data will be performed in order to carry out a more reliable miRNA target identification. This analysis will provide a more efficient criterion to identify the subset of miRNA-mRNA relationships. In order to determine the biological function and the role played during CML pathogenesis of miRNAs deregulated in LSCs, miRNA overexpression and silencing experiments will be performed. MiRNA overexpressed in LSCs will be inhibited in the same cell population to evaluate their involvement in the pathogenesis of leukemia. In the same way, miRNAs down regulated in LSCs will be inhibited in normal HSCs.
Moreover, we plan to analyse the mechanisms that are responsible for miRNAs aberrant expression in CML stem cell compartment. First, the identification of BCR-ABL- independent miRNAs aberrant expression will add a new layer of complexity to CML pathogenesis and will provide new potential targets for CML therapy. Moreover, it’s been recently demonstrated that epigenetic modifications could represent a mechanism to regulate miRNAs expression. Therefore methylation analysis on promoter region of miRNAs deregulated in CML stem cells will allow us to understand whether an epigenetic mechanism is responsible for miRNAs aberrant expression, thus suggesting that treatment with chromatin modifying agents could represent a novel therapeutic strategy for CML patients.
Conclusion: The integrated study of the gene expression and miRNA expression profile of CML stem cells compared to their normal counterparts represents a powerful tool to better understand the role of miRNAs aberrant expression in the pathogenesis of CML. The proposed project will allow us to identify microRNAs which expression is disrupted in CML LSCs. The characterization of deregulated miRNAs in CML LSCs will enable us to identify new regulatory mechanisms involved in CML pathogenesis that could represent new potential targets for CML therapeutics.