Lucia Catani

1) The pathogenetic role of the inflammatory microenvironment in the Myeloproliferative Neoplasms (MPNs)

A) ROLE OF CIRCULATING EXTRACELLULR VESICLES IN THE INFLAMMATORY MICROENVIRONMENT of MPN

The aim of the study is to evaluate the role of circulating extracellular vesicles  in Mielofibrosis and how the inflammatory microenvironment can modulate their bio-molecular and functional pattern. In addition, it has been evaluated whether the circulating megakaryocyte- and platelet-derived extracellular vesicles can be considered as a new biomarker of response to Ruxolitinib (a JAK ½ inhibitor).

Published manuscripts

1) Circulating megakaryocyte and platelet microvesicles correlate with response to ruxolitinib and distinct disease severity in patients with Myelofibrosis. Barone M, Ricci F, Sollazzo D, Ottaviani E, Romano M, Auteri G, Bartoletti D, Reggiani MLB, Vianelli N, Tazzari PL, Cavo M, Forte D, Palandri F, Catani L. Br J Haematol. 2019 Jun;185(5):987-991. doi: 10.1111/bjh.15682.

2) Distinct Profile of CD34⁺ Cells and Plasma-Derived Extracellular Vesicles from Triple-Negative Patients with Myelofibrosis Reveals Potential Markers of Aggressive Disease. Dorian Forte, Martina Barone, Cristina Morsiani, Daria Sollazzo, Giorgia Simonetti, Francesco Fabbri, Samantha Bruno, Maria Chiara Deregibus, Giuseppe Auteri, Emanuela Ottaviani, Nicola Vianelli, Giovanni Camussi, Miriam Capri, Francesca Palandri, Michele Cavo and Lucia Catani. J Exp Clin Cancer Res. 2021 Feb 1;40(1):49. doi: 10.1186/s13046-020-01776-8.

The study is ongoing. In particular, the experimental hypothesis is based on the identification of new biomarkers of disease progression and therapeutic targets through the study of the lipidomic and proteomic profile of the circulating extracellular vesicles of patients with MPN

B) NEW ACQUISITIONS ON THE IMMUNE MICROENVIRONMENT OF MPN

Objective A) 1) To evaluate in patients with Mielofibrosis the phenotypic/functional pattern of subpopulations with crucial role in immunity; 2) correlate the number/phenotype of the immune subtypes with the circulating level of selected pro-inflammatory cytokines. Overall, we have shown that in the course of Mielofibrosis, driver mutations (JAK2, CALR) are associated with phenotypic and functional alterations in different immune subgroups. Such alterations may have a potential role in the progression of the disease and susceptibility to infections.

Published manuscripts:

• Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in Myelofibrosis. Marco Romano, Daria Sollazzo, Sara Trabanelli, Martina Barone, Nicola Polverelli, Margherita Perricone, Dorian Forte, Simona Luatti, Michele Cavo, Nicola Vianelli, Camilla Jandusc, Francesca Palandri and Lucia Catani. Oncoimmunology 2017

Objective B): This project aims to investigate the in vitro biological / functional effects of the inhibitor of JAK 1/2 Ruxolitinib on circulating monocytes by MPN patients including Myelofibrosis

• The Role of Circulating Monocytes and JAK Inhibition in the Infectious-Driven Inflammatory Response of Myelofibrosis. Martina Barone, Lucia Catani, Francesca Ricci, Marco Romano, Dorian Forte, Giuseppe Auteri, Daniela Bartoletti, Emanuela Ottaviani, Pier Luigi Tazzari, Nicola Vianelli, Michele Cavo, Francesca Palandri. Oncoimmunology. 2020 Jun 23;9(1):1782575. doi: 10.1080/2162402X.2020.1782575

The study is ongoing. In particular, we aim to characterize the immunophenotype of circulating and bone marrow CD34+/myelomonocytic cells of MPN patients for the detection of prognostic and predictive immunophenotypic biomarkers.

In particular, the experimental design will be articulated as follows:

1. To develop and validate a multicolor FCI assay for MPN, which includes immunophenotypic markers for the characterization of CD34+ cells (CD45, CD34, CD13, CD117, CD33, HLA-DR, CD7, CD38) and myelomonocytic cells (CD14, CD64, CD56, HLA -DR, CD16);
2. To test whether the immunophenotypic markers of point 1 are expressed by circulating extracellular vesicles
3. To evaluate and compare the immunophenotype of circulating and BM CD34+/myelomonocytic cell of MPN patients at diagnosis or baseline and after 3, 6, 12 months of standard treatment (Hydroxyurea, IFN alpha, Ruxolitinib (JAK 1/2 inhibitor)) or novel therapeutic approaches (Fedratinib, Momelotinib, Pacritinib (second generation JAK inhibitors).
4. To correlate the immunophenotype data with the clinical and laboratory data, and with treatment response.

C) ROLE OF CHRONIC INFLAMMATION IN THE PATHOGENESIS OF MPNs : IN VITRO BIOMOLECULAR AND FUNCTIONAL ANALYSIS OF THE STEM PROGENITOR CELLS

Objectives:

The main hypothesis of this project is that the in vitro analysis of the biological/ molecular effects of selected pro-inflammatory molecules on hematopoietic stem/progenitors CELLS will contribute to clarifying the role of the inflammatory micro-environment in MPN pathogenesis and acute leukemia.

Published manuscripts:

• In vitro study of the malignant hemopoietic clone of myelofibrosis (IL-1β / TNF-α / TIMP-1), the crucial factors of the inflammatory microenvironment (IL-1β / TNF-α / TIMP-1). Pumpkin D, D Fort, Polverelli N, Romano M, Perricone M, Rossi L, Ottaviani E, Luates S, Martinelli G, Vianelli N, Cable M, Palandri F, Catani L. Oncotarget. 2016 Jul 12; 7 (28): 43974-43988

• Circulating Calreticulin Is Increased in Myelofibrosis: Correlation with Interleukin-6 Plasma Levels, Bone Marrow Fibrosis, and Splenomegaly. Pumpkin D, D Fort, Polverelli N, Perricone M, Romano M, Luates S, Vianelli N, M Cable, Palandri F, Catani L. Mediators Inflamm. 2016; 2016: 5,860,657

• The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes the survival and migration of acute myeloid leukemia cells through CD63 / PI3K / Akt / p21 signaling. Forte D, Salvestrini V, Corradi G, Red L, Catani L, Lemoli RM, Cable M, Curves A. Oncotarget. 2017 Jan 10; 8 (2): 2261-2274