Ilaria Tanasi
@univr.it
Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area, University of Verona
Azienda Ospedaliera Universitaria Integrata di Verona
Scopus Publications
Scopus Publications
Francesco Malfona, Ilaria Tanasi, Matteo Piccini, Cristina Papayannidis, Vincenzo Federico, Valentina Mancini, Elisa Roncoroni, Elisabetta Todisco, Simona Bianchi, Giulia Ciotti,et al.
Ferrata Storti Foundation (Haematologica)
Not available.
Darina Ocadlikova, Federico Lussana, Nicola Fracchiolla, Massimiliano Bonifacio, Lidia Santoro, Mario Delia, Sabina Chiaretti, Crescenza Pasciolla, Alessandro Cignetti, Fabio Forghieri,et al.
Wiley
SummaryBlinatumomab is the first bi‐specific T‐cell engager approved for relapsed or refractory B‐cell precursor acute lymphoblastic leukaemia (B‐ALL). Despite remarkable clinical results, the effects of blinatumomab on the host immune cell repertoire are not fully elucidated. In the present study, we characterized the peripheral blood (PB) and, for the first time, the bone marrow (BM) immune cell repertoire upon blinatumomab treatment. Twenty‐nine patients with B‐ALL received blinatumomab according to clinical practice. Deep multiparametric flow cytometry was used to characterize lymphoid subsets during the first treatment cycle. Blinatumomab induced a transient redistribution of PB effector T‐cell subsets and Treg cells with a persistent increase in cytotoxic NK cells, which was associated with a transient upregulation of immune checkpoint receptors on PB CD4 and CD8 T‐cell subpopulations and of CD39 expression on suppressive Treg cells. Of note, BM immune T‐cell subsets showed a broader post‐treatment subversion, including the modulation of markers associated with a T‐cell‐exhausted phenotype. In conclusion, our study indicates that blinatumomab differentially modulates the PB and BM immune cell repertoire, which may have relevant clinical implications in the therapeutic setting.
Luca Lanino, Francesco Restuccia, Alessandra Perego, Marta Ubezio, Bruno Fattizzo, Marta Riva, Angela Consagra, Pellegrino Musto, Daniela Cilloni, Esther Natalie Oliva,et al.
Wiley
Vanessa E. Kennedy, Cecelia Perkins, Andreas Reiter, Mohamad Jawhar, Johannes Lübke, Hanneke C. Kluin-Nelemans, William Shomali, Cheryl Langford, Justin Abuel, Olivier Hermine,et al.
American Society of Hematology
Abstract Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had “leukemic MCL” (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.
Davide Lazzarotto, Ilaria Tanasi, Antonella Vitale, Matteo Piccini, Michelina Dargenio, Fabio Giglio, Fabio Forghieri, Nicola Fracchiolla, Marco Cerrano, Elisabetta Todisco,et al.
Springer Science and Business Media LLC
Giacomo Coltro, Emanuela Sant'Antonio, Giuseppe A. Palumbo, Francesco Mannelli, Valerio De Stefano, Marco Ruggeri, Elena M. Elli, Roberta Zanotti, Oscar Borsani, Irene Bertozzi,et al.
Wiley
BACKGROUND
Incorporating real-world data in the drug development process allows the improvement of health outcomes by providing better representation of actual patterns of drug safety and efficacy.
AIMS AND METHODS
Here, we present the results of a retroprospective, observational real-life study of 154 patients with myelofibrosis treated with ruxolitinib in a real-life setting in seven Italian centers of the MYNERVA project.
RESULTS
Median drug exposure was 29 (range, 3-98) months. Discontinuation rate was 27% after a median time of 13 (range, 3-61). While hematological toxicities were in line with previous findings, infections occurred frequently, representing a not negligible cause of discontinuation and death. Anemia, symptoms, and spleen responses were obtained at any time in 23%, 91%, and 68% of patients, respectively; most patients achieved their responses by week 24. Larger splenomegaly and delayed treatment initiation correlated with lower spleen response at 24 weeks. Spleen response was associated with a superior overall survival, regardless of DIPSS. Of interest, both achievement and loss of spleen response had prognostic implications.
DISCUSSION AND CONCLUSION
Overall, our findings provide insights on the efficacy and safety of ruxolitinib in a real-world, multicenter cohort of Italian MF patients.
Michelina Dargenio, Massimiliano Bonifacio, Sabina Chiaretti, Antonella Vitale, Nicola Stefano Fracchiolla, Cristina Papayannidis, Fabio Giglio, Prassede Salutari, Ernesta Audisio, Barbara Scappini,et al.
Wiley
Within the Campus ALL network we analyzed the incidence, characteristics, treatment and outcome of a central nervous system (CNS) relapse in 1035 consecutive adult acute lymphoblastic leukemia (ALL) patients treated frontline with pediatric‐inspired protocols between 2009 and 2020. Seventy‐one patients (6.8%) experienced a CNS recurrence, more frequently in T‐ (28/278; 10%) than in B‐ALL (43/757; 5.7%) (p = 0.017). An early CNS relapse—< 12 months from diagnosis—was observed in 41 patients. In multivariate analysis, risk factors for early CNS relapse included T‐cell phenotype (p = <0.001), hyperleucocytosis >100 × 109/L (p<0.001) and male gender (p = 0.015). Treatment was heterogeneous, including chemotherapy, radiotherapy, intrathecal therapy and novel agents. A complete remission (CR) was obtained in 39 patients (55%) with no differences among strategies. After CR, 26 patients underwent an allogenic transplant, with a significant overall survival benefit compared to non‐transplanted patients (p = 0.012). After a median observation of 8 months from CNS relapse, 23 patients (32%) were alive. In multivariate analysis, the time to CNS relapse was the strongest predictor of a lower 2‐year post‐relapse survival (p<0.001). In conclusion, in adult ALL the outcome after a CNS relapse remains very poor. Effective CNS prophylaxis remains the best approach and allogenic transplant should be pursued when possible.
Francesco Mannelli, Francesca Crupi, Roberta Zanotti, Livio Pagano, Davide Rapezzi, Ilaria Tanasi, Marianna Criscuolo, Massimiliano Bonifacio, Alberto Fresa, Paola Guglielmelli,et al.
SAGE Publications
In systemic mastocytosis, cytoreductive treatment is indicated for advanced systemic mastocytosis (AdvSM) variants. The treatment scenario is rapidly diversifying especially with the introduction of KIT tyrosine kinase inhibitors. Avapritinib is a second-generation potent and selective inhibitor of the mutant KIT D816V that, based on the results of pivotal clinical trials, was approved for the treatment of adults with AdvSM by the regulatory agencies US FDA and EMA. The present article reports the experience of treating SM patients with avapritinib in an Italian compassionate use program. The data from our case series confirm the drug as being active after multiple lines of treatment allowing rapid achievement of profound responses, making it also an effective bridging strategy to allogeneic transplant in eligible patients. However, the anticipated wider use of avapritinib in the near future will require careful monitoring of side effects, especially in heavily pretreated patients.
Riccardo Bazzoni, Ilaria Tanasi, Nice Turazzi, and Mauro Krampera
Oxford University Press (OUP)
Abstract Extracellular vesicles (EVs) are membrane-surrounded cellular particles released by virtually any cell type, containing numerous bioactive molecules, including lipids, proteins, and nucleic acids. EVs act as a very efficient intercellular communication system by releasing their content into target cells, thus affecting their fate and influencing several biological processes. EVs are released both in physiological and pathological conditions, including several types of cancers. In hematological malignancies (HM), EVs have emerged as new critical players, contributing to tumor-to-stroma, stroma-to-tumor, and tumor-to-tumor cell communication. Therefore, EVs have been shown to play a crucial role in the pathogenesis and clinical course of several HM, contributing to tumor development, progression, and drug resistance. Furthermore, tumor EVs can reprogram the bone marrow (BM) microenvironment and turn it into a sanctuary, in which cancer cells suppress both the normal hematopoiesis and the immunological antitumor activity, conferring a therapy-resistant phenotype. Due to their physicochemical characteristics and pro-tumor properties, EVs have been suggested as new diagnostic biomarkers, therapeutic targets, and pharmacological nanocarriers. This review aims to provide an update on the pathogenetic contribution and the putative therapeutic utility of EVs in hematological diseases.
Marco Cerrano, Massimiliano Bonifacio, Matteo Olivi, Antonio Curti, Michele Malagola, Michelina Dargenio, Anna Maria Scattolin, Cristina Papayannidis, Fabio Forghieri, Carmela Gurrieri,et al.
Ferrata Storti Foundation (Haematologica)
Not available.
Eleonora De Bellis, Silvia Imbergamo, Anna Candoni, Albana Liço, Ilaria Tanasi, Endri Mauro, Federico Mosna, Matteo Leoncin, Manuela Stulle, Davide Griguolo,et al.
Elsevier BV
Eleonora De Bellis, Silvia Imbergamo, Anna Candoni, Albana Liço, Ilaria Tanasi, Endri Mauro, Federico Mosna, Matteo Leoncin, Manuela Stulle, Davide Griguolo,et al.
Elsevier BV
Roberta Zanotti, Massimiliano Bonifacio, Cecilia Isolan, Ilaria Tanasi, Lara Crosera, Francesco Olivieri, Giovanni Orsolini, Donatella Schena, and Patrizia Bonadonna
MDPI AG
Systemic mastocytosis (SM) and other adult clonal mast cell disorders (CMD) are often underestimated, and their epidemiology data are scarce. We aimed at evaluating the impact of the activity of the Interdisciplinary Group for Study of Mastocytosis (GISM) of Verona on the prevalence and incidence of CMD. We examined the data of 502 adult patients diagnosed with CMD and residing in the Veneto Region, consecutively referred to GISM between 2006 and 2020. SM was diagnosed in 431 cases, while 71 patients had cutaneous mastocytosis or other CMD. Indolent SM represented the most frequent SM variant (91.0%), mainly with the characteristics of bone marrow mastocytosis (54.8%). The prevalence of SM in the adult population of the Veneto region and of the Verona province was 10.2 and 17.2/100,000 inhabitants, respectively. The mean incidence of new SM cases in Verona was 1.09/100,000 inhabitants/year. Hymenoptera venom allergy was the main reason (50%) leading to the CMD diagnosis. Osteoporosis, often complicated by fragility fractures, was present in 35% of cases, even in young patients, especially males. Our data show a higher prevalence and incidence of SM than previously reported, confirming that reference centers with multidisciplinary approach are essential for the recognition and early diagnosis of CMD.
Massimiliano Bonifacio, Mario Tiribelli, Maria Cristina Miggiano, Elisabetta Abruzzese, Gianni Binotto, Luigi Scaffidi, Maddalena Cordioli, Daniela Damiani, Eros Di Bona, Malgorzata Monika Trawinska,et al.
Wiley
Patients with hematological malignancies are at an increased risk of SARS‐CoV‐2 disease (COVID‐19) and adverse outcome. However, a low mortality rate has been reported in patients with chronic myeloid leukemia (CML). Preclinical evidence suggests that tyrosine kinase inhibitors (TKIs) may have a protective role against severe COVID‐19.
Ilaria Tanasi, Elisa Olivieri, Margherita Oberti, Giuseppe Lucchini, Fabiana Furci, Roberta Zanotti, and Patrizia Bonadonna
Elsevier BV
Carlo Visco, Francesca Pregnolato, Isacco Ferrarini, Beatrice De Marco, Valentina Bonuomo, Eugenio Sbisà, Costanza Fraenza, Andrea Bernardelli, Ilaria Tanasi, Francesca Maria Quaglia,et al.
Elsevier BV
Ilaria Tanasi, Massimiliano Bonifacio, Miriam Pizzolato, Federica Irene Grifoni, Mariarita Sciumè, Chiara Elena, Pietro Benvenuti, Francesco Mannelli, Roberta Parente, Donatella Schena,et al.
Wiley
Mastocytosis represents a group of clonal disorders characterized by abnormal proliferation and infiltration of mast cells in various tissues, particularly skin and haematopoietic organs, ranging from skin-limited diseases to systemic and more aggressive variants. Its clonal nature relies on somatic, gain-of-function mutations in exon 17, causing constitutive activation of the c-KIT proto-oncogene and detected in most patients. More than 80% of adult patients with a systemic disease carry a somatic aspartate-to-valine substitution in codon 816 (D816V) of the KIT gene. Although it is a putative, non-hereditary disease, familial cases have been reported in paediatric series, with an estimated frequency of 11–13%. However, data about the familial occurrence in adults are still lacking. This retrospective, observational, multicentre study aimed first at assessing the prevalence of familial disease in a large cohort of adult patients with mastocytosis and, second, at describing the clinical and molecular features of familial cases. Our cohort included 1541 adult patients followed by eight Italian Institutions, diagnosed with systemic or cutaneous mastocytosis, according to 2016 WHO criteria. All patients were asked about the occurrence of mastocytosis in relatives. When achievable, KIT mutational status was assessed both in index patients and relatives. Clinical data were collected retrospectively. Informed consent was obtained from participants, according to the guidelines of the local ethics committee Azienda Ospedaliera Universitaria Integrata di Verona. Among 1541 patients, we identified 23 clustered cases, resulting in an estimated prevalence of 1 5% familial cases. The median age at diagnosis of index patients was 44 years (range 16–70). Diagnosis was systemic mastocytosis (SM) in 16 cases (69 5%) and cutaneous mastocytosis (CM) in four cases (17 4%). Three patients (13 6%) who refused bone marrow biopsy were diagnosed with mastocytosis in the skin (MIS). Ten out of 16 SM patients (62 5%) had indolent systemic mastocytosis (ISM), four (25%) had bone marrow mastocytosis (BMM), one had aggressive SM (ASM) and one had systemic mastocytosis with associated haematological neoplasm (SM-AHN). KIT D816V mutation was found in either bone marrow (BM) or peripheral blood (PB) in all but one patient with SM (93 7%). Relatives with mastocytosis had a median age at diagnosis of 20 years (range 0–70), i.e., they were younger than the index cases. Seven patients (30 4%) had SM (ISM, n = 3; SM-AHN, n = 2; smouldering systemic mastocytosis (SSM), n = 1; BMM, n = 1); 13 patients (52 2%) had a cutaneous variant of mastocytosis [maculo-papular cutaneous mastocytosis (MPCM), n = 7; cutaneous mastocytoma, n = 6] and three patients had a diagnosis of MIS. The KIT mutational status was available only in four of seven relatives with SM, and three of them were KIT D816V mutated; five relatives with MPCM and one with MIS were negative for KIT D816V mutation in BM or PB. In eight out of 23 clustered cases, the KIT mutational status had been assessed in BM in both index patient and relative: concordant results were documented only in four out of eight cases, three D816V mutated and one wild-type. In the remaining cases, the index case carried the D816V mutation, whereas the relative was found to be negative. Finally, the index/relative relationships were: eight out of 23 parent and child (34 8%), eight out of 23 siblings (34 8%) and seven out of 23 other relationship (30 4%). Index and relative patients’ clinical and molecular characteristics are listed in Table I. In our series, the clinical phenotype was highly heterogeneous, without any clear correlation in the disease presentation among members of the same familial cluster (see Fig 1). Moreover, 11 out of 23 clustered cases (47 8%) had the disease onset during adulthood, whereas in six cases (26 1%) symptoms appeared in childhood. In six families (26 1%) symptoms appeared either in childhood in the index case and in adulthood in relative or vice versa. Finally, in one case, both the index patient and her sister had an SM-AHN, associated with a triple-negative myeloproliferative neoplasm (MPN) and chronic myeloid leukaemia (CML), respectively. In the index case, the KIT D816V mutation was detected in PB, whereas neither the mutational status nor symptoms’ age at onset was available for the relative. To our knowledge, this is the largest report on the prevalence and characteristics of familial mastocytosis in an adult population. Interestingly, in most of our index cases, we identified the KIT D816V mutation, which has never been shown to be inherited. Familial cases described so far were mainly paediatric CM lacking KIT lesions or harbouring uncommon KIT mutations, often positioned outside the exon 17 (i.e. A533D, K509I). Both somatic and germline KIT mutations have been reported in a few familial cases of gastrointestinal stromal tumor and mastocytosis. Our group and Broesby-Olsen et al. have correspondence
Roberta Zanotti, Ilaria Tanasi, Andrea Bernardelli, Giovanni Orsolini, and Patrizia Bonadonna
MDPI AG
Bone marrow mastocytosis (BMM) represents a provisional, indolent subvariant of systemic mastocytosis (SM). Utilizing WHO criteria, BMM requires bone marrow (BM) involvement and the absence of mastocytosis skin lesions. BMM is characterized by male sex prevalence, a slight increase of serum tryptase levels, low BM mast cells (MC) burden, and an indolent clinical course. BMM shows a strong correlation with severe anaphylaxis, mainly due to an IgE-mediated allergy to bee or wasp venom and, less frequently, to unexplained (idiopathic) anaphylaxis. Furthermore, BMM is often associated with osteoporosis which could be the only presenting symptom of the disease. BMM is an undervalued disease as serum tryptase levels are not routinely measured in the presence of unexplained osteoporosis or anaphylaxis. Moreover, BMM patients are often symptom-free except for severe allergic reactions. These factors, along with typical low BM MCs infiltration, may contribute to physicians overlooking BMM diagnosis, especially in medical centers that lack appropriately sensitive diagnostic techniques. This review highlights the need for a correct diagnostic pathway to diagnose BMM in patients with suspected symptoms but lacking typical skin lesions, even in the case of normal serum tryptase levels. Early diagnosis may prevent potential life-threatening anaphylaxis or severe skeletal complications.
Javier I Muñoz-González, Iván Álvarez-Twose, María Jara-Acevedo, Roberta Zanotti, Cecelia Perkins, Mohamad Jawhar, Wolfgang R Sperr, Khalid Shoumariyeh, Juliana Schwaab, Georg Greiner,et al.
Elsevier BV
Paul Takam Kamga, Riccardo Bazzoni, Giada Dal Collo, Adriana Cassaro, Ilaria Tanasi, Anna Russignan, Cristina Tecchio, and Mauro Krampera
Frontiers Media SA
Notch and Wnt signaling are highly conserved intercellular communication pathways involved in developmental processes, such as hematopoiesis. Even though data from literature support a role for these two pathways in both physiological hematopoiesis and leukemia, there are still many controversies concerning the nature of their contribution. Early studies, strengthened by findings from T-cell acute lymphoblastic leukemia (T-ALL), have focused their investigation on the mutations in genes encoding for components of the pathways, with limited results except for B-cell chronic lymphocytic leukemia (CLL); in because in other leukemia the two pathways could be hyper-expressed without genetic abnormalities. As normal and malignant hematopoiesis require close and complex interactions between hematopoietic cells and specialized bone marrow (BM) niche cells, recent studies have focused on the role of Notch and Wnt signaling in the context of normal crosstalk between hematopoietic/leukemia cells and stromal components. Amongst the latter, mesenchymal stromal/stem cells (MSCs) play a pivotal role as multipotent non-hematopoietic cells capable of giving rise to most of the BM niche stromal cells, including fibroblasts, adipocytes, and osteocytes. Indeed, MSCs express and secrete a broad pattern of bioactive molecules, including Notch and Wnt molecules, that support all the phases of the hematopoiesis, including self-renewal, proliferation and differentiation. Herein, we provide an overview on recent advances on the contribution of MSC-derived Notch and Wnt signaling to hematopoiesis and leukemia development.
Roberta Zanotti, Massimiliano Bonifacio, Ilaria Tanasi, Donatella Schena, Giovanni Orsolini, Morena Tebaldi, Lara Crosera, Francesca Mastropaolo, Elisa Olivieri, and Patrizia Bonadonna
Institute of Hematology, Catholic University
Systemic mastocytosis (SM) is a heterogeneous group of diseases that affect almost exclusively adults and are defined by the proliferation and accumulation of clonal mast cells (MC) in various tissues. Disease subtypes range from indolent to rare but aggressive forms. Although SM is classified as a rare disease, it is believed to be likely underdiagnosed. Major signs and symptoms mainly depend on MC activation and less frequently to organ infiltration, typical of more aggressive variants. Diagnosis may be challenging, and symptoms can be aspecific and involve several organs. It is advisable to refer patients to specialized centers, having sufficient knowledge of the disease, sensitive diagnostic procedures, offering a personalized and multidisciplinary diagnostic approach, including at least hematological, allergological, dermatological and rheumatological evaluations. A precise and timely diagnosis is required for: a) adequate counseling of patients and their physicians; b) beginning of symptomatic treatment (anti-mediator therapy); c) prevention of severe manifestations of the disease (i.e., recurrent anaphylaxis, osteoporosis and bone fractures); d) cytoreductive treatment of advanced SM variants.
 This review aims to summarize the main manifestations of the disease and describe the ideal diagnostic approach for adult patients with suspected SM, giving physicians the main notions for correct patient diagnosis and management. This review also highlights the importance of a multidisciplinary approach in this very complex disease.
Riccardo Bazzoni, Paul Takam Kamga, Ilaria Tanasi, and Mauro Krampera
Frontiers Media SA
Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in the stromal tissues of the body and capable of promoting tissue repair and attenuating inflammatory processes through their immunomodulatory properties. Preclinical and clinical observations revealed that not only direct intercellular communication mediates MSC properties; in fact, a pivotal role is also played by the release of soluble and bioactive factors, such as cytokines, growth factor and extracellular vesicles (EVs). EVs are membrane-coated vesicles containing a large variety of bioactive molecules, including lipids, proteins, and nucleic acids, such as RNA. EVs release their contents into target cells, thus influencing cell fate through the control of intracellular processes. In addition, MSC-derived EVs can mediate modulatory effects toward different effector cells belonging to both innate and adaptive immunity. In this review, we will discuss the literature data concerning MSC-derived EVs, including the current standardized methods for their isolation and characterization, the mechanisms supporting their immunoregulatory properties, and their potential clinical application as alternative to MSC-based therapy for inflammatory reactions, such as graft-versus-host disease (GvHD).
Carlo Visco, Ilaria Tanasi, Francesca Maria Quaglia, Isacco Ferrarini, Costanza Fraenza, and Mauro Krampera
MDPI AG
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma in adults. Despite the recognition of transcriptional subtypes with distinct functional characteristics, patient outcomes have not been substantially altered since the advent of chemoimmunotherapy (CIT) twenty years ago. Recently, a few pivotal studies added to the disease heterogeneity by describing several activating mutations, which have been associated with disease presentation, B-cell function and behavior, and final outcome. DLBCL arises from antigen exposed B-cells, with the B-cell receptor (BCR) playing a central role. BCR-activity related mutations, such as CD79B and MYD88, are responsible for chronic activation of the BCR in a substantial subset of patients. These mutations, often coexisting in the same patient, have been found in a substantial subset of patients with immune-privileged (IP) sites DLBCLs, and are drivers of lymphoma development conferring tissue-specific homing properties. Both mutations have been associated with disease behavior, including tumor response either to CIT or to BCR-targeted therapy. The recognition of CD79B and MYD88 mutations will contribute to the heterogeneity of the disease, both in recognizing the BCR as a potential therapeutic target and in providing genetic tools for personalized treatment.
Paul Takam Kamga, Giada Dal Collo, Adriana Cassaro, Riccardo Bazzoni, Pietro Delfino, Annalisa Adamo, Alice Bonato, Carmine Carbone, Ilaria Tanasi, Massimiliano Bonifacio,et al.
MDPI AG
Wnt/β-catenin signaling has been reported in Acute Myeloid leukemia, but little is known about its significance as a prognostic biomarker and drug target. In this study, we first evaluated the correlation between expression levels of Wnt molecules and clinical outcome. Then, we studied—in vitro and in vivo—the anti-leukemic value of combinatorial treatment between Wnt inhibitors and classic anti-leukemia drugs. Higher levels of β-catenin, Ser675-phospho-β-catenin and GSK-3α (total and Ser 9) were found in AML cells from intermediate or poor risk patients; nevertheless, patients presenting high activity of Wnt/β-catenin displayed shorter progression-free survival (PFS) according to univariate analysis. In vitro, many pharmacological inhibitors of Wnt signalling, i.e., LRP6 (Niclosamide), GSK-3 (LiCl, AR-A014418), and TCF/LEF (PNU-74654) but not Porcupine (IWP-2), significantly reduced proliferation and improved the drug sensitivity of AML cells cultured alone or in the presence of bone marrow stromal cells. In vivo, PNU-74654, Niclosamide and LiCl administration significantly reduced the bone marrow leukemic burden acting synergistically with Ara-C, thus improving mouse survival. Overall, our study demonstrates the antileukemic role of Wnt/β-catenin inhibition that may represent a potential new therapeutics strategy in AML.
Ilaria Tanasi, Annalisa Adamo, Paul Takam Kamga, Riccardo Bazzoni, and Mauro Krampera
Elsevier BV