Publications by authors named "Mauro Nanni"

47 Publications

The complex karyotype landscape in chronic lymphocytic leukemia allows to refine the risk of Richter syndrome transformation.

Haematologica 2021 Jun 3. Epub 2021 Jun 3.

Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy; Veneto Institute of Molecular Medicine, Padua.

Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural abnormalities) or high-CK (CK with C5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter reallife retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q-/TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; while mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (p<0.0001). We herein demonstrated that CK landscape at CLL diagnosis allows to refine the risk of RS transformation and we recapitulated clinico-biological variables into a prognostic model.
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http://dx.doi.org/10.3324/haematol.2021.278304DOI Listing
June 2021

Balanced and unbalanced chromosomal translocations in myelodysplastic syndromes: clinical and prognostic significance.

Leuk Lymphoma 2020 12 1;61(14):3476-3483. Epub 2020 Sep 1.

Hematology, Dipartimento Medicina Traslazionale e di Precisione, AOU Policlinico Umberto I Sapienza University of Rome, Rome, Italy.

Prognostic role of chromosomal translocations (CT) in myelodysplasia (MDS) was retrospectively analyzed in 77 patients from GROM-L registry. Forty (51.9%) balanced, 28 (36.4%) unbalanced and 9 (11.7%) concomitant balanced and unbalanced CT were identified. Five-year overall survival (OS) of the entire cohort was 34.5% (CI 95% 22.5-46.5). Five-year OS of patients with unbalanced CT was significantly shorter than that of patients carrying balanced CT [22.3% (CI 95% 4.0-40.6) vs 44.0% (CI 95% 26.7-61.3) ( = 0.042)]. Five-year OS of patients with CT included in complex karyotype (CK) was significantly shorter than that of patients with isolated CT or CT with another abnormality [5.5% (CI 95% 0-15.7) vs 42.9% (CI 95% 21.3-64.5) and vs 4% (CI 95% 31.6-79.2) ( < 0.001)]. Presence of CT in MDS characterizes a more aggressive outcome only when associated with CK.
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http://dx.doi.org/10.1080/10428194.2020.1811861DOI Listing
December 2020

Atypical Chronic Myeloid Leukemia in a Patient with Aplastic Anemia.

Acta Haematol 2019 21;142(3):185-186. Epub 2019 May 21.

Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1159/000497137DOI Listing
February 2020

Clinical relevance of hypogammaglobulinemia, clinical and biologic variables on the infection risk and outcome of patients with stage A chronic lymphocytic leukemia.

Leuk Res 2017 06 27;57:65-71. Epub 2017 Feb 27.

Hematology Section, Cosenza Hospital, Cosenza, Italy.

The prognostic effect of hypogammaglobulinemia (HGG), clinical and biologic characteristics on the infection risk and outcome has been retrospectively analyzed in 899 patients with stage A chronic lymphocytic leukemia (CLL). Low levels of IgG were recorded in 19.9% of patients at presentation, low levels of IgM and/or IgA in 10.4% and an additional 20% of patients developed HGG during the course of the disease. Before the start of any treatment, 160 (12.9%) patients experienced at least one grade ≥3 infection requiring a systemic anti-infective treatment and/or hospitalization. While IgG levels at diagnosis were not associated with an increased risk of grade ≥3 infection or with an adverse outcome, a significantly increased rate of grade ≥3 infections was recorded in patients with unmutated IGHV (p=0.011) and unfavorable FISH aberrations (p=0.009). Late onset HGG, more frequently recorded in patients with Rai stage I-II (p=0.001) and unmutated IGHV (p=0.001), was also associated with a higher rate of severe infections (p=0.002). These data indicate that, stage A patients with clinical and biologic characteristics of a more aggressive disease develop more frequently late onset HGG, grade ≥3 infections and require a closer clinical monitoring.
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http://dx.doi.org/10.1016/j.leukres.2017.02.011DOI Listing
June 2017

A VLBI experiment using a remote atomic clock via a coherent fibre link.

Sci Rep 2017 02 1;7:40992. Epub 2017 Feb 1.

Istituto Nazionale di Ricerca Metrologica, INRIM, Strada delle Cacce 91, 10135 Torino, Italy.

We describe a VLBI experiment in which, for the first time, the clock reference is delivered from a National Metrology Institute to a radio telescope using a coherent fibre link 550 km long. The experiment consisted of a 24-hours long geodetic campaign, performed by a network of European telescopes; in one of those (Medicina, Italy) the local clock was alternated with a signal generated from an optical comb slaved to a fibre-disseminated optical signal. The quality of the results obtained with this facility and with the local clock is similar: interferometric fringes were detected throughout the whole 24-hours period and it was possible to obtain a solution whose residuals are comparable to those obtained with the local clock. These results encourage further investigation of the ultimate VLBI performances achievable using fibre dissemination at the highest precision of state-of-the-art atomic clocks.
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http://dx.doi.org/10.1038/srep40992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286532PMC
February 2017

Fludarabine, cyclophosphamide and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia. A multicenter phase I-II GIMEMA trial.

Leuk Lymphoma 2017 07 23;58(7):1640-1647. Epub 2016 Nov 23.

a Department of Cellular Biotechnologies and Hematology, Hematology , Sapienza University , Rome , Italy.

The activity and safety of a regimen combining lenalidomide with fludarabine and cyclophosphamide (FC) was investigated in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Treatment consisted of six monthly courses of the FC regimen combined with 14 days of lenalidomide given at the starting dose of 2.5 mg during course 1. The maximum tolerated dose of lenalidomide was 5 mg. Forty patients were assessed for response, 66% were IGHV unmutated, 45% showed deletion 11q or 17p. The overall response and complete remission rates were 62.5% and 22.5%, respectively, the median progression-free and overall survival (OS) were 19 and 45 months, respectively. Grade 3-4 granulocytopenia was observed in 65% of cases, severe infections in 7.5%, the lenalidomide-related toxicity was mild. In conclusion, the results of this study demonstrate that low-dose lenalidomide associated with the FC schedule is an effective treatment for R/R patients with CLL, associated with an acceptable safety profile.
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http://dx.doi.org/10.1080/10428194.2016.1258698DOI Listing
July 2017

Can chronic myeloid leukaemia in children and adolescents be successfully treated without haematopoietic stem cell transplant? A single centre experience.

Br J Haematol 2016 06 23;173(5):749-53. Epub 2016 Feb 23.

Haematology, Department of Cellular Biotechologies and Haematology, "Sapienza" University, Rome, Italy.

We analysed the long-term outcome of 35 children and adolescents (<20 years at diagnosis) with chronic myeloid leukaemia (CML) in chronic phase: 20 patients had received interferon-alpha and/or tyrosine kinase inhibitors (TKIs), and 15 underwent a haematopoietic stem cell transplant. The 10-year survival probabilities were similar in transplanted and non-transplanted patients (73·3% vs. 72·1%, respectively), whereas the survival probability was significantly lower in patients diagnosed before 1999 compared to those diagnosed afterwards (62·1% vs. 100%, P = 0·0384). The availability of TKIs and the standardized molecular monitoring have significantly improved treatment, management and outcome in children and adolescents with CML.
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http://dx.doi.org/10.1111/bjh.13991DOI Listing
June 2016

Impact of exclusion criteria for the DASISION and ENESTnd trials in the front-line treatment of a 'real-life' patient population with chronic myeloid leukaemia.

Hematol Oncol 2017 Jun 9;35(2):232-236. Epub 2015 Dec 9.

Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Rome, Italy.

Both Dasision and ENESTnd trials had many exclusion criteria, with a possible selection bias compared with the real-life. To address the impact of this bias on the first-line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase chronic myeloid leukaemia (CML) patients [M/F 108/99, median age 58.8 years, interquartile range 42.3-70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution, and evaluated how many of them would have been excluded from enrolment in the two trials. Twenty-eight patients (13.5%) should have been excluded by both trials because of polycomorbidities (12), severe cardiomyopathy (five), age > 80 with frailty (three), drug abuse (two) or other severe concomitant diseases (six). In addition, eight patients should have been excluded by Dasision due to isolated chronic obstructive broncopulmonar disease, and 19 patients should have been excluded by ENESTnd due to isolated diabetes (10), arrhythmia (four), acute myocardial infarction > 6 months before CML diagnosis (two), chronic pancreatic disease (two) and peripheral arterial obstructive disease (one). On the whole, 36 patients (17.4%) would have been excluded by Dasision trial and 47 (22.7%) by ENESTnd trial. The patients potentially not eligible for both trials were significantly older and with imatinib had a worse outcome compared with patients potentially eligible. Our data highlight that an automatic transposition of results available in clinical controlled trials into the frontline real-life management of CML patients should be regarded with caution. Copyright © 2015 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/hon.2274DOI Listing
June 2017

Inter- and intra-patient clonal and subclonal heterogeneity of chronic lymphocytic leukaemia: evidences from circulating and lymph nodal compartments.

Br J Haematol 2016 Feb 24;172(3):371-383. Epub 2015 Nov 24.

Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.

Whole exome sequencing and copy number aberration (CNA) analysis were performed on cells taken from peripheral blood (PB) and lymph nodes (LN) of patients with chronic lymphocytic leukaemia (CLL). Of 64 non-silent somatic mutations, 54 (84·4%) were clonal in both compartments, 3 (4·7%) were PB-specific and 7 (10·9%) were LN-specific. Most of the LN- or PB-specific mutations were subclonal in the other corresponding compartment (variant frequency 0·5-5·3%). Of 41 CNAs, 27 (65·8%) were shared by both compartments and 7 (17·1%) were LN- or PB-specific. Overall, 6 of 9 cases (66·7%) showed genomic differences between the compartments. At subsequent relapse, Case 10, with 6 LN-specific lesions, and Case 100, with 6 LN-specific and 8 PB-specific lesions, showed, in the PB, the clonal expansion of LN-derived lesions with an adverse impact: SF3B1 mutation, BIRC3 deletion, del8(p23·3-p11·1), del9(p24·3-p13·1) and gain 2(p25·3-p14). CLL shows an intra-patient clonal heterogeneity according to the disease compartment, with both LN and PB-specific mutations/CNAs. The LN microenvironment might contribute to the clonal selection of unfavourable lesions, as LN-derived mutations/CNAs can appear in the PB at relapse.
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http://dx.doi.org/10.1111/bjh.13859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732889PMC
February 2016

Long-term results of high-dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience.

Br J Haematol 2015 Aug 20;170(3):398-407. Epub 2015 Apr 20.

Haematology, Department of Cellular Biotechnologies and Haematology, 'Sapienza' University, Rome, Italy.

Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long-term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long-term results of high-dose IM (340 mg/m2 /d) in CML patients in chronic phase (CP-CML) aged <18 years at diagnosis. A total of 47 CP-CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91.5% of the evaluable patients at a median time of 6 months. BCR-ABL1 International Scale ≤ 0.1% (major molecular response; MMR) and ≤0.01% (molecular response; MR) at 12 months were 66.6% and 33%, respectively. During follow-up, MMR and MR were achieved in 78.6% and 61% of children, respectively. IM was safely discontinued in 3 long-term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression-free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow-up of 52 months (range 3-146), all patients are alive. High-dose IM is a long-term effective therapy in children and adolescents with CP-CML.
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http://dx.doi.org/10.1111/bjh.13453DOI Listing
August 2015

Fludarabine plus alemtuzumab (FA) front-line treatment in young patients with chronic lymphocytic leukemia (CLL) and an adverse biologic profile.

Leuk Res 2014 Feb 19;38(2):198-203. Epub 2013 Nov 19.

Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.

In 45, ≤ 60 years old patients with CLL and an adverse biologic profile, a front-line treatment with Fludarabine and Campath (Alemtuzumab(®)) was given. The overall response rate was 75.5%, the complete response rate (CR) 24.4% with the lowest CR rates, 16.7% and 8.3%, in 11q and 17p deleted cases. The 3-year progression-free survival (PFS) and overall survival were 42.5% and 79.9%, respectively. PFS was significantly influenced by CLL duration, beta2-microglobulin, and improved by post-remissional stem cell transplantation. Front-line fludarabine and alemtuzumab showed a manageable safety profile and evidence of a benefit in a small series of CLL patients with adverse biologic features.
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http://dx.doi.org/10.1016/j.leukres.2013.11.009DOI Listing
February 2014

Stereotyped subset #1 chronic lymphocytic leukemia: a direct link between B-cell receptor structure, function, and patients' prognosis.

Am J Hematol 2014 Jan;89(1):74-82

Chronic lymphocytic leukemia (CLL) with stereotyped B-cell receptor (BCR) belonging to subset #1 (IGHV1-5-7/ IGKV1-39) display a poor outcome. To characterize their genetic and genomic features and BCR function, we selected 20 subset #1 CLL from a series of 579 cases. Subset #1 CLL, all showing unmutated IGHV, were associated with the presence of del(11q) (50%) in comparison with unmutated CLL, unmutated stereotyped CLL other than subset #1 and with cases using the same IGHV genes but a heterogeneous VH CDR3 (non-subset #1 CLL). There were no distinctive features regarding CD38, ZAP-70, and TP53 disruption. NOTCH1, SF3B1, and BIRC3 were mutated in 15%, 0%, and 5% of cases, respectively, while BIRC3 was deleted in 22% of cases. Microarray unsupervised analysis on 80 unmutated/mutated/stereotyped/non-stereotyped CLL showed a tight clustering of subset #1 cases. Their genomic signature exhibited several differentially expressed transcripts involved in BCR signal transduction, apoptosis regulation, cell proliferation, and oxidative processes, regardless of del(11q). Accordingly, BCR ligation with anti-IgM revealed a significant higher proliferation of subset #1 versus unmutated non-subset #1 CLL, both at baseline and after 24–48 hr stimulation. Subset #1 CLL represent a paradigmatic example of the direct link between BCR structure, function, and patients prognosis.
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http://dx.doi.org/10.1002/ajh.23591DOI Listing
January 2014

Complete clearance of Ph+ metaphases after 3 months is a very early indicator of good response to imatinib as front-line treatment in chronic myelogenous leukemia.

Acta Haematol 2013 28;129(2):126-34. Epub 2012 Nov 28.

Department of Cellular Biotechnology and Hematology, La Sapienza University, Rome, Italy.

Aim: To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph- metaphases (MET-, when <20 cells were evaluable).

Methods: We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011.

Results: After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET- while 44 patients (24.2%) still presented Ph+ metaphases (MET+) (<33%, 24 patients; ≥33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 × 10(9)/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET- at 3 months. Among patients with CCyR/MET- after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/MET- at 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET- at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001).

Conclusions: The achievement of CCyR/MET- at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines.
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http://dx.doi.org/10.1159/000343384DOI Listing
April 2013

Prognostic features of patients with myelodysplastic syndromes aged < 50 years: update of a single-institution experience.

Leuk Lymphoma 2012 Dec 9;53(12):2439-43. Epub 2012 Jul 9.

Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.

Fewer than 10% of patients with myelodysplastic syndromes (MDS) are younger than 50 years. A series of 91 younger patients (median age 44 years with female prevalence) are reported and compared with elderly patients. Frequent karyotypic changes were trisomy 8 (9.8%) and monosomy 7 (5%). Twenty-three patients had occupational exposure to potential mutagens (benzene and solvents), with a male predominance, higher frequency of refractory cytopenia with multilineage dysplasia (RCMD) (52%) and higher frequency of monosomy 7 (21.7%). At a median follow-up of 72 months, 22 patients (24%) evolved to acute leukemia, with higher frequency being observed among the exposed cohort (39% vs. 19% non-exposed). Unfavorable factors for overall survival were: age > 40 years, > 5% of blasts, trilinear bone marrow involvement and intermediate-high World Health Organization Prognostic Scoring System (WPSS) risk. The present results suggest that younger MDS could be identified as a distinct subset. For patients belonging to the low/intermediate-I risk group, due to a low transformation rate, aggressive approaches should rarely be recommended.
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http://dx.doi.org/10.3109/10428194.2012.698738DOI Listing
December 2012

Polycombs and microRNA-223 regulate human granulopoiesis by transcriptional control of target gene expression.

Blood 2012 Apr 10;119(17):4034-46. Epub 2012 Feb 10.

San Raffaele Bio-medical Park Foundation, Rome, Italy.

Epigenetic modifications regulate developmental genes involved in stem cell identity and lineage choice. NFI-A is a posttranscriptional microRNA-223 (miR-223) target directing human hematopoietic progenitor lineage decision: NFI-A induction or silencing boosts erythropoiesis or granulopoiesis, respectively. Here we show that NFI-A promoter silencing, which allows granulopoiesis, is guaranteed by epigenetic events, including the resolution of opposing chromatin "bivalent domains," hypermethylation, recruitment of polycomb (PcG)-RNAi complexes, and miR-223 promoter targeting activity. During granulopoiesis, miR-223 localizes inside the nucleus and targets the NFI-A promoter region containing PcGs binding sites and miR-223 complementary DNA sequences, evolutionarily conserved in mammalians. Remarkably, both the integrity of the PcGs-RNAi complex and DNA sequences matching the seed region of miR-223 are required to induce NFI-A transcriptional silencing. Moreover, ectopic miR-223 expression in human myeloid progenitors causes heterochromatic repression of NFI-A gene and channels granulopoiesis, whereas its stable knockdown produces the opposite effects. Our findings indicate that, besides the regulation of translation of mRNA targets, endogenous miRs can affect gene expression at the transcriptional level, functioning in a critical interface between chromatin remodeling complexes and the genome to direct fate lineage determination of hematopoietic progenitors.
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http://dx.doi.org/10.1182/blood-2011-08-371344DOI Listing
April 2012

Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biologic features, treatment, and long-term outcome.

Blood 2012 Mar 18;119(10):2219-27. Epub 2012 Jan 18.

Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.

Sixty-four patients < 20 years of age, investigated for a suspicion of Philadelphia-negative myeloproliferative disease (MPD), were retrospectively evaluated to characterize the different forms and to examine the treatments used and long-term outcome. JAK2 mutations, endogenous erythroid colony growth, and clonality were investigated in 51 children. Mutations of thrombopoietin, the thrombopoietin receptor (MPL), and the erythropoietin receptor and mutations of other genes involved in the pathogenesis of MPD were investigated in JAK2 wild-type patients. Based on our criteria for childhood MPD, we identified 34 patients with sporadic thrombocythemia (ST), 16 with hereditary thrombocytosis (HT), 11 with sporadic polycythemia (SP), and 3 with hereditary polycythemia (HP). JAK2(V617F) mutations were present in 47.5% of ST and in no HT. The MPL(S505A) mutation was detected in 15/16 HT patients and in no ST (P < .00001). The JAK2(V617F) mutation occurred in 27% of SP patients diagnosed according to the Polycythemia Vera Study Group or World Health Organization 2001 criteria. Children with ST received more cytoreductive drugs than those with HT (P = .0006). After a median follow-up of 124 months, no patient had developed leukemia or myelofibrosis and 5% had thrombosis; the miscarriage rate in thrombocythemic patients was 14%. The low complication rate in our population suggests that children with MPD may be managed by tailored approaches.
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http://dx.doi.org/10.1182/blood-2011-08-371328DOI Listing
March 2012

Behind the scenes of non-nodal MCL: downmodulation of genes involved in actin cytoskeleton organization, cell projection, cell adhesion, tumour invasion, TP53 pathway and mutated status of immunoglobulin heavy chain genes.

Br J Haematol 2012 Mar 8;156(5):601-11. Epub 2011 Dec 8.

Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.

Mantle cell lymphoma (MCL) is an aggressive neoplasm with a short survival. Cases with leukaemic MCL and splenomegaly without adenopathies (non-nodal MCL) may have a more indolent course. To gain insights into the biological features underlying this presentation, we investigated the gene expression profile (GEP) and the IGHV mutational status in a cohort of leukaemic MCL cases. Comparison of MCL with other lymphoproliferative disorders (i.e. splenic marginal zone lymphoma, follicular lymphoma, chronic lymphocytic leukaemia) revealed a MCL signature enriched for the following gene categories: mitochondrion, oxidoreductase activity, response to stress, to DNA damage and TP53-pathway. Furthermore, GEP analysis revealed that non-nodal MCL cases were characterized by the down-modulation of the following gene categories: cell projection, actin cytoskeleton organization, cell adhesion (ITGAE, CELSR1, PCDH9) and tumour invasion/progression (PGF, ST14, ETS1, OCIAD1, EZR). Many down-modulated genes were related to the TP53-pathway and to DNA damage response. IGHV status proved unmutated in all nodal and mutated in all non-nodal MCL. Non-nodal leukaemic MCLs display a peculiar clinical presentation, with distinctive biological features, such as mutated IGHV and a transcriptional profile lacking tumour invasion properties, that might contribute to the absence of nodal involvement and to the less aggressive clinical course.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08962.xDOI Listing
March 2012

ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression.

Haematologica 2012 Jan 11;97(1):47-55. Epub 2011 Oct 11.

Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.

Background: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease.

Design And Methods: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval.

Results: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations.

Conclusions: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.
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http://dx.doi.org/10.3324/haematol.2011.049270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248930PMC
January 2012

5'-Azacitidine for therapy-related myelodysplastic syndromes after non-Hodgkin lymphoma treatment.

Leuk Res 2011 Oct 15;35(10):1409-11. Epub 2011 Jun 15.

Department of Cellular Biotechnologies and Hematology, Sapienza University, Via Benevento 6, 00161 Rome, Italy.

Therapy-related myelodysplastic syndromes are possible complications in patients treated for previous hematologic malignancies. Therapeutic strategies in these type of disorders are still not well defined: azacitidine has been recently approved for the treatment of higher risk myelodysplastic syndromes, but few data are published relating possible efficacy in therapy-related dysplastic disorders. We reported here 4 patients treated with azacitidine for therapy related dysplasia after chemotherapy for non-Hodgkin lymphoma.
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http://dx.doi.org/10.1016/j.leukres.2011.05.030DOI Listing
October 2011

13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia.

Genes Chromosomes Cancer 2011 Aug 11;50(8):633-43. Epub 2011 May 11.

Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy.

Deletion at 13q14 is detected by fluorescence in situ hybridization (FISH) in about 50% of chronic lymphocytic leukemia (CLL). Although CLL with 13q deletion as the sole cytogenetic abnormality (del13q-only) usually have good prognosis, more aggressive clinical courses are documented for del13q-only CLL carrying higher percentages of 13q deleted nuclei. Moreover, deletion at 13q of different sizes have been described, whose prognostic significance is still unknown. In a multi-institutional cohort of 342 del13q-only cases and in a consecutive unselected cohort of 265 CLL, we investigated the prognostic significance of 13q deletion, using the 13q FISH probes locus-specific identifier (LSI)-D13S319 and LSI-RB1 that detect the DLEU2/MIR15A/MIR16-1 and RB1 loci, respectively. Results indicated that both percentage of deleted nuclei and presence of larger deletions involving the RB1 locus cooperated to refine the prognosis of del13q-only cases. In particular, CLL carrying <70% of 13q deleted nuclei with deletions not comprising the RB1 locus were characterized by particularly long time-to-treatment. Conversely, CLL with 13q deletion in <70% of nuclei but involving the RB1 locus, or CLL carrying 13q deletion in ≥70% of nuclei, with or without RB1 deletions, collectively experienced shorter time-to-treatment. A revised flowchart for the prognostic FISH assessment of del13q-only CLL, implying the usage of both 13q probes, is proposed.
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http://dx.doi.org/10.1002/gcc.20885DOI Listing
August 2011

Evaluation of TP53 mutations with the AmpliChip p53 research test in chronic lymphocytic leukemia: correlation with clinical outcome and gene expression profiling.

Genes Chromosomes Cancer 2011 Apr 13;50(4):263-74. Epub 2011 Jan 13.

Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.

Given that TP53 alterations predict prognosis and response to therapy in chronic lymphocytic leukemia (CLL), screening for TP53 mutations has an increasing role in patient management. TP53 direct sequencing is a time-consuming method, while the AmpliChip p53 Research Test is a novel non time-consuming microarray-based resequencing assay and queries Exons 2-11. We evaluated the impact of TP53 mutations on clinical outcome by analyzing 98 untreated CLL using the AmpliChip p53 Research Test and direct sequencing and performed microarrays analysis on TP53 mutated and/or deleted cases. The AmpliChip p53 Research Test detected 17 mutations in 14 patients (17.3%); a significant association between TP53 mutations and del(17p) was recorded. From a clinical standpoint, a higher percentage of mutation was found in CLL with unfavorable outcome (17.2% vs. 7.1% in progressive vs. stable cases). Detection of TP53 mutations by the AmpliChip p53 Research Test was associated with a significantly worse survival (P = 0.0002). Comparison of the array and direct sequencing tests showed that the p53 Research Test detected more mutations, although it failed to identify two microdeletions. Finally, microarrays analysis showed a more distinctive signature associated with del(17p) than with TP53 mutations, likely due to a concomitant gene dosage effect. The AmpliChip p53 Research Test is a straightforward method that bears prognostic value. This study confirms a high percentage of TP53 mutations in CLL with unfavorable outcome and a significant association between TP53 aberrations and del(17p). Finally, specific gene expression profiles are recognized for TP53 alterations.
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http://dx.doi.org/10.1002/gcc.20852DOI Listing
April 2011
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