Giulia Falconi - Academia.edu (original) (raw)

Papers by Giulia Falconi

Mediterranean Journal of Hematology and Infectious Diseases

Therapy-related myeloid neoplasms (t-MN) are a late complication of cytotoxic therapy (CT) used i... more Therapy-related myeloid neoplasms (t-MN) are a late complication of cytotoxic therapy (CT) used in the treatment of both malignant and non-malignant diseases. Historically, t-MN has been considered to be a direct consequence of DNA damage induced in normal hematopoietic stem or progenitor cells (HSPC) by CT. However, we now know that treatment-induced mutations in HSC are not the only players involved in t-MN development but additional factors may contribute to the onset of t-MN. One of the known drivers involved in this field is the bone marrow microenvironment (BMM) and in particular bone marrow mesenchymal stem cells (BM-MSC) whose role in t-MN pathogenesis is the topic of this mini-review. BM-MSC, physiologically, support HSC maintenance, self-renewal, and differentiation, through hematopoietic–stromal interactions and production of cytokines. In addition, BM-MSC maintain the stability of the BM immune microenvironment and reduce the damage caused to HSC by stress stimuli. In t-...

Inflammation Research, Jul 28, 2023

Objective and design Systemic-Inflammatory-Autoimmune-Diseases (SIAD) is increasingly considered ... more Objective and design Systemic-Inflammatory-Autoimmune-Diseases (SIAD) is increasingly considered in Myelodysplastic-Syndromes (MDS). In this line, we evaluated the MDS auto-immunological profile, correlating it to the mutational landscape, trying to identify a molecular-genetic trigger agent related to SIAD. Methods and materials Eighty-one MDS were enrolled and t-NGS was performed. Anti-Nuclear-Antibodies (ANA) were tested, and ANA-antigenic-specificity was characterized by ANA-profile, ENA-screen, anti-dsDNA. Non-Hematological-Patients (NHP) and Healthy-Donors (HD) were used as controls. Results At clinically relevant cutoff (≥ 1:160), ANA was significantly more frequent in MDS, while ANA-antigenic-specificity showed a low association rate. ANA ≥ 1:160-positive MDS showed a mutational landscape similar to ANA-negative/ ANA < 1:160 MDS. No significant correlations between mutational and immunological profiles were found and UBA1 mutations, related to VEXAS, were absent. Conclusions Although ANA-positivity was found to be increased in MDS, the low ANA-antigenic-specificity suggests that autoantibodies didn't recognize autoimmune-pathognomonic antigens. The lack of relationship between genetic profile and ANA-positivity, suggests that MDS genetic variants may not be the direct cause of SIAD. Keywords Anti-nuclear antibodies (ANA) • ANA antigenic specificity • Inflammatory and autoimmune diseases • Myelodysplastic syndromes • VEXAS • Mutational profile • Auto-immunological profile Key message MDS patients showed an increased ANA positivity at clinically relevant cutoff. The low ANA antigenic specificity suggests that autoantibodies didn't recognize autoimmune-pathognomonic antigens. Lack of correlation between mutational-landscape and ANA suggests that somatic variants aren't involved in SIAD.

Current Research in Translational Medicine, Apr 1, 2023

Current Research in Translational Medicine

British Journal of Haematology, 2022

Clonal haematopoiesis of indeterminate potential (CHIP) may predispose for the development of the... more Clonal haematopoiesis of indeterminate potential (CHIP) may predispose for the development of therapy-related myeloid neoplasms (t-MN). Using target next-generation sequencing (t-NGS) panels and digital droplet polymerase chain reactions (ddPCR), we studied the myeloid gene mutation profiles of patients with chronic lymphocytic leukaemia (CLL) who developed a t-MN after treatment with chemo-(immuno)therapy. Using NGS, we detected a total of 30 pathogenic/likely pathogenic (P/LP) variants in 10 of 13 patients with a t-MN (77%, median number of variants for patient: 2, range 0-6). The prevalence of CHIP was then backtracked in paired samples taken at CLL diagnosis in eight of these patients. Six of them carried at least one CHIP-variant at the time of t-MN (median: 2, range: 1-5), and the same variants were present in the CLL sample in five cases. CHIP variants were present in 34 of 285 patients from a population-based CLL cohort, which translates into a significantly higher prevalence of CHIP in patients with a CLL who developed a t-MN, compared to the population-based cohort (5/8, 62.5% vs. 34/285, 12%, p = 0.0001). Our data show that CHIP may be considered as a novel parameter affecting treatment algorithms in patients with CLL, and highlight the potential of using chemo-free therapies in CHIP-positive cases.

Blood cancer journal, Jan 3, 2015

Scientific Reports

Bone marrow mesenchymal stem cells (BM-MSCs) exhibit multiple abnormalities in myelodysplastic sy... more Bone marrow mesenchymal stem cells (BM-MSCs) exhibit multiple abnormalities in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), including reduced proliferative and clonogenic capacity, altered morphology, impaired immunoregulatory properties and capacity to support hematopoiesis. Here, we investigated expression of the FOXM1 gene, a transcription factor driving G2/M gene expression, in BM-MSCs isolated from patients with MDS and AML, de novo and therapy-related, compared to BM-MSCs isolated from healthy donors (HD). We observed a statistically significant downregulation of FOXM1 expression in BM-MSCs isolated from MDS and AML patients, as compared to controls. In parallel, expression of FOXM1 mitotic targets (CCNB1, CDC20, PLK1 and NDC80) was suppressed in patients’ BM-MSCs, as compared to HD. No differences in the expression of FOXM1 and its mitotic targets were observed in BM-mononuclear cells from the different sources. From a functional standpoint, silencing of...

$Research paper thumbnail of GSK3\u3b2 down-regulation in Mesenchymal Stem Cells from patients with Myelodysplastic Syndrome$

In addition to neoplastic transformation of hematopoietic progenitors,bone marrow microenvironmen... more In addition to neoplastic transformation of hematopoietic progenitors,bone marrow microenvironment damages can contribute to myeloid neoplasms development and maintenance. Several functional and morphological abnormalities of bone marrow mesenchymal stromal cells (BM-MSC) have been described in myeloid neoplasms. Nevertheless, molecular bases of differences between MSCs from normal and leukemic/myelodysplastic bone marrows are still unknown. Deregulation of genes belonging to PI3K/AKT signaling pathway has been described in MSC from different type of cancers. We studied the expression profile of genes belonging to PI3K/AKT signaling pathway in MSCs from 40 patients including 10 de novo AML, 10 de novo MDS, 10 t-MN (therapy-related myeloid neoplasms) and 10 patients with limited stage lymphoma without bone marrow involvement (used as normal control). BM-MSCs were obtained by Ficoll-gradient centrifugation of bone marrow samples and cultured up to 70% confluence in MesenCult Medium. C...

Leukemia Research

T including the role of erythroblast membrane lipid rafts, and alterations in Pro-and Anti-apopto... more T including the role of erythroblast membrane lipid rafts, and alterations in Pro-and Anti-apoptotic signals, such as Fas expression. Pro-inflammatory proteins, as S100A9 and TNF-α and, finally, pathways other than EPO-signaling, like Kit-ligand, may also impair erythropoiesis in MDS, as non-redundant factors.

Leukemia, 2019

Treatment outcomes in patients with newly diagnosed acute promyelocytic leukemia (APL) has dramat... more Treatment outcomes in patients with newly diagnosed acute promyelocytic leukemia (APL) has dramatically improved in the past two decades, following the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA combined with chemotherapy (CHT) results in cure rates above 80%; however, it is associated with significant shortand long-term toxicity, including the risk of secondary leukemias. ATO combined with ATRA is significantly more active than conventional CHT in APL [1, 2], and has more manageable toxic effects. Despite these advances, mechanisms of resistance to ATRA-CHT and to ATRA-ATO, although infrequent, remain elusive. Recent investigations, including one from our group [3], suggested that the presence of point mutations in the two moieties of the PML/RARA hybrid may play a role in resistance to therapy. In keeping with this hypothesis, mutations of the PML-B2 domain of PML/RARA have been shown to prevent ATO binding, inhibiting degradation of the oncoprotein, thus hindering oligomerization into nuclear bodies [4]. In particular, the PML-A216V mutation, the most commonly

Frontiers in Oncology

Acute promyelocytic leukemia (APL) accounts for 10–15% of newly diagnosed acute myeloid leukemias... more Acute promyelocytic leukemia (APL) accounts for 10–15% of newly diagnosed acute myeloid leukemias (AML) and is typically caused by the fusion of promyelocytic leukemia with retinoic acid receptor α (RARA) gene. The prognosis is excellent, thanks to the all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination therapy. A small percentage of APLs (around 2%) is caused by atypical transcripts, most of which involve RARA or other members of retinoic acid receptors (RARB or RARG). The diagnosis of these forms is difficult, and clinical management is still a challenge for the physician due to variable response rates to ATRA and ATO. Herein we review variant APL cases reported in literature, including genetic landscape, incidence of coagulopathy and differentiation syndrome, frequent causes of morbidity and mortality in these patients, sensitivity to ATRA, ATO, and chemotherapy, and outcome. We also focus on non-RAR rearrangements, complex rearrangements (involving more than tw...

The New England Journal of Medicine, May 26, 2022

Thrombocytopenia is a severe complication for patients with myelodysplastic syndrome (MDS). Eltro... more Thrombocytopenia is a severe complication for patients with myelodysplastic syndrome (MDS). Eltrombopag increases platelet count in MDS patients but its combination with azacitidine elicited controversial results. We aimed to quantify the colony forming units of megakaryocytes (CFU-Mk) obtained from CD34+ bone marrow cells isolated from patients with MDS and from healthy donors that were cultured <i>in vitro</i> in the presence or absence of azacitidine and with or without the sequential addition of eltrombopag to the culture medium. CD34+ bone marrow cells from 6 MDS patients and 3 controls were expanded <i>in vitro</i> and cultured for 3 days with or without azacitidine. Subsequently, a CFU-Mk assay was performed in presence or absence of eltrombopag. The addition of eltrombopag in the CFU-Mk assay after mock treatment of CD34+ cells increased the number of CFU-Mk in both controls and patients. On the contrary, using azacitidine pretreated CD34+ cells, eltr...

Myelodysplastic syndromes (MDS) are characterized by altered methylation patterns, with frequent ... more Myelodysplastic syndromes (MDS) are characterized by altered methylation patterns, with frequent methylation of CpG islands of tumor suppressor gene promoter regions, and hyper- and hypomethylation in CpG islands not included in promoter regions and in intercoding sequences [1,2]. In recent years, hypomethylating agents have produced encouraging results in terms of complete and partial responses (CR and PR), delayed leukemia progression and prolonged overall survival in the setting of higher-risk MDS [3,4]. Interestingly, there is not a clear correlation between hypermethylation of CpG islands at the promoter level and clinical response, nor between baseline methylation and hypomethylating drug response, suggesting a wider mechanism of action of these treatments and a complex interaction among drugs, host polymorphisms and methylation patterns [5]. Aberrant hypermethylation is also a frequent feature of therapy-related myeloid neoplasms (t-MN), including t-MDS and t-acute myeloid le...

Hematology/Oncology and Stem Cell Therapy, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Leukemia, 2018

Somatic mutations have been shown to play a significant prognostic role in myelodysplastic syndro... more Somatic mutations have been shown to play a significant prognostic role in myelodysplastic syndromes (MDS). Actually, detection of a TP53, EZH2, RUNX1, ASXL1, or ETV6 mutation predicts rapid disease progression and may direct treatment choices in all MDS subgroups, also in the context of allogeneic stem cell transplantation (HSCT)

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American journal of hematology, Jan 8, 2018

Leukemia Research, 2017

This study focuses on comparative error analysis in English writing made by different levels. To ... more This study focuses on comparative error analysis in English writing made by different levels. To investigate the error types, the frequency of error types, the similarities and difference of errors and the last to find the error sources that occur in first, second and third year learners. Error analysis is one type of linguistic study and it focuses on learners' error making. The linguistic category and surface strategy taxonomy are used to find out the types of error. The analysis the phenomenon based on Brown (1980) namely, error identification, error classification, Error description and error explanation. The data from students' writing products, 54 pieces in three levels and the total errors are 571 erroneous sentences. There are two types of errors, namely lexical errors and syntactical errors; eight error categories and twenty-seven error cases. The second year learners made the most error 263 errors or 46, 05% while first year learners produced 229 errors or 40, 10% and third year learners made 79 errors or 13, 83%. There are similarity in errors types, five similar categories and five error cases, but there are three different error categories and eighteen error cases. The main error sources, learners had lack knowledge of English grammatical rule. The overgeneralization (265 errors or 46, 40%) influences learners' error, language transfer (199 errors or 34, 85%) still interfere learners' acquisition and simplification