Francesca Pavesi
@asst-valleolona.it
Hematology and Stem Cell Transplantation Division - Oncology Department
ASST Valle Olona - Ospedale di Busto Arsizio
RESEARCH, TEACHING, or OTHER INTERESTS
Hematology, Biochemistry, Genetics and Molecular Biology
Scopus Publications
Scopus Publications
Matteo Maria Naldini, Gabriele Casirati, Matteo Barcella, Paola Maria Vittoria Rancoita, Andrea Cosentino, Carolina Caserta, Francesca Pavesi, Erika Zonari, Giacomo Desantis, Diego Gilioli,et al.
Springer Science and Business Media LLC
AbstractAcute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts.
Carolina Caserta, Silvia Nucera, Matteo Barcella, Grazia Fazio, Matteo Maria Naldini, Riccardo Pagani, Francesca Pavesi, Giacomo Desantis, Erika Zonari, Mariella D’Angiò,et al.
Springer Science and Business Media LLC
Maria Teresa Lupo-Stanghellini, Simona Piemontese, Andrea Assanelli, Fabio Serpenti, Sara Mastaglio, Daniela Clerici, Fabio Giglio, Raffaella Greco, Francesca Lorentino, Francesca Pavesi,et al.
Wiley
Elisabetta Xue, Francesca Lorentino, Francesca Pavesi, Andrea Assanelli, Jacopo Peccatori, Massimo Bernardi, Consuelo Corti, Fabio Ciceri, and Maria Teresa Lupo Stanghellini
Elsevier BV
Raffaella Greco, Francesca Lorentino, Serena Albanese, Maria Teresa Lupo Stanghellini, Fabio Giglio, Simona Piemontese, Daniela Clerici, Lorenzo Lazzari, Magda Marcatti, Sara Mastaglio,et al.
Elsevier BV
Daniela Clerici, Chiara Oltolini, Raffaella Greco, Marco Ripa, Fabio Giglio, Sara Mastaglio, Francesca Lorentino, Francesca Pavesi, Francesca Farina, Carmine Liberatore,et al.
Elsevier BV
Fabio Guolo, Luana Fianchi, Paola Minetto, Marino Clavio, Michele Gottardi, Sara Galimberti, Giuliana Rizzuto, Michela Rondoni, Giambattista Bertani, Michela Dargenio,et al.
Springer Science and Business Media LLC
AbstractSecondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.
Rocco Piazza, Vera Magistroni, Sara Redaelli, Mario Mauri, Luca Massimino, Alessandro Sessa, Marco Peronaci, Maciej Lalowski, Rabah Soliymani, Caterina Mezzatesta,et al.
Springer Science and Business Media LLC
AbstractSETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel–Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel–Giedion syndrome caused by SETBP1 mutations.
Chiara Cattaneo, P. Zappasodi, V. Mancini, C. Annaloro, F. Pavesi, C. Skert, A. Ferrario, E. Todisco, V. Saccà, L. Verga,et al.
Springer Science and Business Media LLC
Massimo Bernardi, Matteo Carrabba, Carlo Messina, Raffaella Milani, Elisa Sala, Francesca Pavesi, Bernhard Gentner, Jacopo Peccatori, Andrea Assanelli, Sarah Marktel,et al.
Wiley
To the Editor: The outcome of elderly patients (pts) with acute myeloid leukemia (AML) is unsatisfactory. Median overall survival (OS) of pts older than 65 after intensive treatments is about 6 months and 5-year overall survival is 5–25% [1,2]. Cytogenetics is the most important factor affecting the prognosis of younger pts who receive an intensive treatment. The majority of AML pts presents intermediate-risk (INT) cytogenetics, including normal karyotype (NK) AML which represents about 50% of total cases. Most common molecular abnormalities, NPM1 or CEBPA mutations and/or internal tandem duplication of FLT3, affect the prognosis in younger pts [3]. For clinical practice, the European LeukemiaNet (ELN) proposed a four group standardized genetic prognostic system correlating cytogenetic and molecular data with clinical data, with the INT categories representing 49% of cases of the older pts population [3]. As information about the prognostic impact of genetic abnormalities is limited in older pts the decision to treat them with intensive programs according to their genetic risk is still controversial, in particular for cases with INT characteristics. We retrospectively analyzed data from 77 elderly pts treated at the San Raffaele Institute, fulfilling the following inclusion criteria: age> 65 years, new diagnosis of AML, consecutively considered “fit” for aggressive treatment according to local criteria, receiving at least one cycle of induction chemotherapy between October 2001 and August 2015. General criteria for elegibility were PS (ECOG) 2, renal and hepatic parameters< 2 ULN, left ventricular ejection fraction 50%, absence of uncontrolled infections and concomitant malignancies. Response evaluations were defined according to the IWG revised recommendations [4]. We compared the outcome of pts according to the cytogenetic and ELN genetic risk-groups. Categorical data were compared using the Fisher’s exact test, survival was estimated using the Kaplan–Meier method, the log-rank test was used to compare the survival distributions of different groups of pts. Cytogenetic analysis was evaluable in 68 pts (88%), according to the revised MRC classification [5]. ELN genetic classification could be defined in 46 cases (60%) (Table I). Outcome analysis: 44 pts with NK AML were compared to pts with INT karyotype (other than NK), adverse (ADV), and not evaluable (NE) cytogenetics, analyzed together (no-NK, 31 pts), the 2 only pts with FAV cytogenetics were excluded from this analysis; 24 ELN FAV 1 INT I cases were compared to 22 INT II 1 ADV ones. Complete remission (CR) after induction: 70% (54 pts) overall, NK 82% (36 pts) and no-NK 58% (18 pts) (P 5 0.036), FAV 1 INT I 87% (21 pts) and INT II 1 ADV 54% (12 pts) (P 5 0.021). Fifty-five pts received postremission treatments, 54 pts with high-dose cytarabine (HDARAC, 8 g/sqm total dose) with or without subsequent autologous (AUTO) or allogeneic (ALLO) transplantation (SCT). Pts alive at last follow-up: overall 22/77 (29%) 19 in CR, NK 16/44 (36%) 13 in CR, no-NK 5/31 (16%) 4 in CR (P 5 0.07), FAV 1 INT I 13/24 (54%) 12 in CR, INT II 1 ADV 4/22 (18%) all in CR (P 5 0.015). Median OS from diagnosis for all 77 pts was 437 days (12–4,621), for NK and no-NK pts was 675 (20–4351) and 298 (12–1,585) days, respectively, projected 5 years OS was 40% and 27%, respectively (P 5 0.0019) (Fig. 1A). The difference remained significative also excluding from the analysis the 8 pts with ADV cytogenetics (P 5 0.0044). Median and estimated 5-year OS were still significatively better for NK than for no-NK AML pts excluding from the analysis cases with FAV (P 5 0.0040) or FAV and ADV (P 5 0.0084) molecular abnormalities. Median disease free survival (DFS) for NK and no-NK pts was 519 and 311 days, respectively (P 5 ns). Median OS from diagnosis for FAV 1 INT I and INT II 1 ADV pts was 614 (42–4,638) and 313 (12–1453) days and projected 5 years OS was 48% and 0%, respectively (P 5 0.035) (Fig. 1B). Median DFS for FAV 1 INT I and INT II 1 ADV pts was 293 and 379 days, respectively (P 5 ns). A major challenge for clinicians is identification of elderly pts who would likely benefit from intensive treatments. Our retrospective analysis was aimed in particular to evaluate the outcomes of cases with INT genetic characteristics. Initial selection of our pts was based according to simple clinical and functional evaluations. Pts considered “fit” and with ADV risk cytogenetics were not excluded from intensive treatment programs. Of note, the relatively low frequency of ADV cytogenetics in the study population may reflect an impact of genetic characteristics on the fitness at diagnosis. Our analysis evidenced a better response to induction and better OS for pts with NK AML, either compared to other cytogeneticrisk groups or when evaluated within the ELN classification. In fact, 92% of lower-risk ELN cases (22/24 FAV 1 INT I) were NK AML, while only 25% (11/44) of NK AML cases