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167. ACTIVATION-INDUCED CYTIDINE DEAMINASE IS ABERRANTLY OVEREXPRESSED IN BCRABL1 POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA CELLS AND PROMOTES DNA-SINGLE STRAND BREAKS

Author

Iacobucci, I., Lonetti, A., Ferrari, A., Soverini, S., Ottaviani, E., Testoni, N., Colarossi, S., Salmi, F., Gnani, A., Paolini, S., Piccaluga, P. P., CRISTINA PAPAYANNIDIS, Panagiota, G., Cilloni, D., Messa, F., Pane, F., Vitale, A., Chiaretti, S., Saglio, G., Foa, R., Baccarani, M., Martinelli, G., Iacobucci I, Lonetti A, Ferrari A, Soverini S, Ottaviani E, Testoni N, Colarossi S, Salmi F, Gnani A, Paolini S, Piccaluga PP, Papayannidis C, Panagiota G, Cilloni D, Messa F, Pane F, Vitale A, Chiaretti S, Saglio G, Foà R, Baccarani M, and Martinelli G

Subjects
hemic and lymphatic diseases, ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID), PHILADELPHIA-POSITIVE LEUKEMIAS
Abstract

The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 kinase and defines a subgroup of ALL with a particularly unfavorable prognosis. ALL cells derived from B cell precursors typically carry rearranged immunoglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on expression of activationinduced cytidine deaminase (AID), which introduces single-strand breaks into target DNA. Since, at much lower frequency AID can also target non-Ig genes and may even act as a genome-wide mutator, we investigated whether AID was expressed in Ph+ ALL and blast crisis chronic myeloid leukemia (CML) patients. On 35 adult Ph+ ALL patients, we detected AID mRNA and protein in 16 (46%), moreover AID expression was also found in blast crisis B-lymphoid lineage CML patients (n=2) but not in myeloid lineage (n=5) or in chronic phase CML (n=30). AID expression correlated with the BCR-ABL1 transcript levels and with the frequency of mutations within the BCR-ABL1 kinase domain that confer resistance to the BCR-ABL1 kinase inhibitors and disappeared after treatment with imatinib at the time of remission. To investigate whether AID introduces DNA-SSB in Ph+ ALL, we performed a genome wide analysis by 250K NspI single nucleotide polymorphism (SNP) array (Affymetrix Inc., USA) which is able to detect at high resolution and throughout the genome copy number abnormalities. We identified region of high level amplification and homozygous deletion in all patients. Overall, deletions outnumbered amplifications 3:1 and on average, we found 10 lesions per case, with a median of 6 losses and 2 gains. Patients who expressed AID had a higher number of alterations respect to patients who were AID negative (median copy number alteration was 8.5, range 4-22, versus 4, range 1-10, respectively, p

Published
2008

173. Mechanisms accounting for lymphocytic alveolitis in hypersensitivity pneumonitis

Author

Trentin, L., Migone, N., Zambello, R., Di Celle, P. F., Aina, F., Feruglio, C., Bulian, P., Masciarelli, M., Carlo Agostini, Cipriani, A., Marcer, G., Foa, R., Pizzolo, G., and Semenzato, G.

Subjects
Adult, Cytotoxicity, Immunologic, Receptors, Antigen, T-Cell, alpha-beta, Immunology, Receptors, Antigen, T-Cell, Receptors, Antigen, T-Cell, gamma-delta, Receptors, Interleukin-2, HLA-DR Antigens, Blotting, Northern, Flow Cytometry, Gene Rearrangement, T-Lymphocyte, Lymphocyte Activation, Pulmonary Alveoli, Blotting, Southern, Antigens, CD, Receptors, Very Late Antigen, Humans, Interleukin-2, Immunology and Allergy, Bronchoalveolar Lavage Fluid, Alveolitis, Extrinsic Allergic
Abstract

Hypersensitivity pneumonitis (HP) is a lung disorder characterized by an exaggerated accumulation of CD8+ T lymphocytes in the pulmonary parenchyma. To investigate the mechanisms accounting for the T cell alveolitis taking place in the lung of HP patients and their pattern of growth, cells recovered from the bronchoalveolar lavage (BAL) of seven patients were evaluated for: 1) the expression of activation markers, including IL-2R (p55 and p75 subunits), HLA-DR and VLA-1 Ag; 2) the ability of IL-2 and IL-4 to induce in vitro proliferation; 3) the capability to synthesize and release IL-2 by determining the levels of IL-2 in BAL cell-free supernatants and by evaluating the presence of mRNA transcripts for IL-2; and 4) the molecular configuration of the beta- and gamma-genes of the TCR. This study demonstrates that a high number of BAL lymphocytes recovered from the lungs of HP patients express activation markers including the p75 chain of IL-2R, VLA-1, and HLA-DR Ag. These cells express the CD3+,CD8+,CD16-,CD56+ phenotype and proliferate in vitro in the presence of IL-2 but do not release this cytokine. Furthermore, IL-2 transcripts could not be detected in BAL resting T lymphocytes. No proliferation was observed in the presence of IL-4. The analysis of the configuration of the TCR beta- and gamma-genes showed a polyclonal pattern, with the exception of one case in which extra bands were observed following digestion with BamHI and EcoRI restriction enzymes. Taken together, our data suggest that the IL-2 system may play a central role in the mechanisms accounting for lymphocytic alveolitis in HP patients. Although the pattern of growth is usually polyclonal, such polyclonal recruitment seems to be biased toward cells that have rearranged and possibly expressed particular V beta or V gamma genes, thus leading to the hypothesis that the events that take place in the lung of these patients may occasionally elicit an oligoclonal expansion of the cells proliferating in lung parenchyma.

Published
1990
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180. A prospective phase II study on tandem autografting - Nonmyeloablative allografting for newly diagnosed multiple myeloma: Final results of a multicenter GITMO (Gruppo Italiano Trapianto Midollo Osseo) protocol

Author

Sorasio, R, Patriarca, F, Giaccone, L, Mattei, D, Allione, B, CARNEVALE SCHIANCA, F, Rambaldi, A, Casini, M, Montefusco, V, Parma, M, Bavaro, F, Onida, F, Busca, A, Castagna, L, Lori, Ap, Rotta, M, Fiore, F, Benedetti, E, Mordini, N, Massaia, M, Palumbo, A, Aglietta, M, Lewis, A, Foa, R, DI BARTOLOMEO, P, Pogliani, E, LAMBERTENGHI DELILIERS, G, Falma, M, Petrini, M, Corradini, F, Fanin, R, Ricardi, U, Ciccone, G, Baldi, Ileana, Bruno, B, and Boccadoro, M.

Published
2007

185. The role of BCR/ABL isoforms in the presentation and outcome of patients with Philadelphia-positive acute lymphoblastic leukemia: a seven-year update of the GIMEMA 0496 trial

Author

Cimino, G, Pane, F, Elia, L, Finolezzi, E, Fazi, P, Annino, L, Meloni, G, Mancini, M, Tedeschi, A, DI RAIMONDO, F, Specchia, G, Fioritoni, G, Leoni, P, Cuneo, A, Mecucci, Cristina, Saglio, G, Mandelli, F, Foa', R, and GIMEMA Leukemia Working Party

Subjects
Adult, Genetic Markers, Treatment Outcome, Multivariate Analysis, Fusion Proteins, bcr-abl, Humans, Multicenter Studies as Topic, Protein Isoforms, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Follow-Up Studies, Proportional Hazards Models, Randomized Controlled Trials as Topic
Abstract

To verify the potential clinical and prognostic value of BCR/ABL isoforms, we analyzed 101 consecutive adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in the GIMEMA 0496 trial between October 1996 and December 1999. A p190 or p210 with or without p190 BCR/ABL transcript was documented in 59 (58.5%) and 42 cases (41.5%), respectively. At diagnosis, a white cell count16 x 10(9)/L and a higher level of CD34 and CD33 expression were associated with the p190 BCR/ABL transcript (p0.05, p=0.009 and p=0.03, respectively). A complete remission was achieved in 62/92 (67.4%) patients, while 16/92 (17.4%) were resistant and 14/92 (15.2%) died of therapy-related complications. Fifty-two patients underwent intensive re-induction treatment, which was followed by stem cell transplant consolidation in the 36 in persistent complete remission (allogeneic = 20 patients; autologous = 16 patients). Response rates to induction therapies were similar in the two BCR/ABL isoform groups. By contrast, the p190 emerged as the only independent prognostic factor favorably affecting the 5-year overall survival and disease-free survival rates (p=0.008 and p=0.02, respectively).

Published
2006

187. High levels of tumor load reduction after intensive chemotherapy favorably affect the prognosis of BCR/ABL plus ALL Adult patients receiving imatinib mesylate alone as a post-consolidation treatment according to the Italian GIMEMA LAL 0201/A protocol

Author

Cimino, Giuseppe, Elia, L., Pane, F., Vignetti, Marco, Fazi, P., Iacobelli, S., Meloni, Giovanna, Vitale, A., Martini, V., Martinelli, G., Di Raimondo, F., Bonifacio, M., Fabbiano, F., Saglio, G., Baccarani, M., Foa, R., and Mandelli, F.

Published
2006

194. Outcome of Allogeneic Stem Cell Transplantation for Patients Transformed to Myelodysplastic Syndrome or Leukemia from Severe Aplastic Anemia: A Report from the MDS Subcommittee of the Chronic Malignancies Working Party and the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation

Author

Hussein, A.A., Halkes, C.M., Socie, G., Tichelli, A., Borne, P.A. von dem, Schaap, M.N., Foa, R., Ganser, A., Dufour, C., Bacigalupo, A., Locasciulli, A., Aljurf, M., Peters, C., Robin, M., Biezen, A.A. van, Volin, L., Witte, T.J. de, Marsh, J., Passweg, J.R., Kroger, N., et al., Hussein, A.A., Halkes, C.M., Socie, G., Tichelli, A., Borne, P.A. von dem, Schaap, M.N., Foa, R., Ganser, A., Dufour, C., Bacigalupo, A., Locasciulli, A., Aljurf, M., Peters, C., Robin, M., Biezen, A.A. van, Volin, L., Witte, T.J. de, Marsh, J., Passweg, J.R., Kroger, N., and et al.

Abstract

Item does not contain fulltext, One hundred and forty patients who had undergone hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) transformation after treatment of severe aplastic anemia (SAA) were identified in the European Group for Blood and Marrow Transplantation (EBMT) database. The median age at HSCT was 29 years (range, 1 to 66 years). The transplant donor was related in 49% cases and unrelated in 51% cases. The 5-year probability of relapse was 17%, and that of nonrelapse mortality was 41%. The 5-year overall survival was 45% +/- 9%, better for patients untreated and patients in remission compared with patients with refractory disease. Our data indicate that allogeneic HSCT leads to prolonged survival in close to one-half of the patients transforming to MDS or AML from SAA.

Published
2014

195. The Last Mile in Analyzing Wellbeing and Poverty : Indices of Social Development

Author

Staveren, I.P. (Irene) van, Webbink, E. (Ellen), Haan, A. (Arjan) de, Foa, R. (Roberto), Staveren, I.P. (Irene) van, Webbink, E. (Ellen), Haan, A. (Arjan) de, and Foa, R. (Roberto)

Abstract

__Abstract__ Development practitioners worldwide increasingly recognize the importance of informal institutions - such as norms of cooperation, non-discrimination, or the role of community oversight in the management of investment activities – in affecting well-being, poverty, and even economic growth. There has been little empirical analysis that tests these relationships at the international level. This is largely due to data limitations: few reliable, globally-representative data sources exist that can provide a basis for cross-country comparison of social norms and practice, social trust and community engagement.

Published
2014
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196. Use of G-CSF to hasten neutrophil recovery after auto-SCT for AML is not associated with increased relapse incidence: a report from the Acute Leukemia Working Party of the EBMT

Author

Czerw, T., Labopin, M., Gorin, N.C., Giebel, S., Blaise, D., Dumas, P.Y., Foa, R., Attal, M., Schaap, N.P., Michallet, M., Bonmati, C., Veelken, H., Mohty, M., Czerw, T., Labopin, M., Gorin, N.C., Giebel, S., Blaise, D., Dumas, P.Y., Foa, R., Attal, M., Schaap, N.P., Michallet, M., Bonmati, C., Veelken, H., and Mohty, M.

Abstract

Contains fulltext : 137156.pdf (publisher's version ) (Closed access), Application of G-CSF in AML is controversial as leukemic blasts may express receptors interacting with the cytokine, which may stimulate leukemia growth. We retrospectively analyzed the impact of G-CSF use to accelerate neutrophil recovery after auto-SCT on outcome. Adults with AML in first CR autografted between 1994 and 2010 were included. Nine hundred and seventy two patients were treated with G-CSF after auto-SCT whereas 1121 were not. BM and PB were used as a source of stem cells in 454 (22%) and 1639 (78%) cases, respectively. The incidence of relapse at 5 years in the BM-auto-SCT group was 38% for patients receiving post-transplant G-CSF and 43% for those not treated with G-CSF, P=0.46. In the PB-auto-SCT cohort, respective probabilities were 48% and 49%, P=0.49. No impact of the use of G-CSF could be demonstrated with respect to the probability of leukemia-free survival: in the BM-auto-SCT group, 51% for G-CSF(+) and 48% for G-CSF(-), P=0.73; in PB-auto-SCT group, 42% for G-CSF(+) and 43% for G-CSF(-), P=0.83. Although G-CSF administration significantly shortened the neutropenic phase, no beneficial effect was observed with regard to non-relapse mortality. In patients with AML, the use of G-CSF after auto-SCT is not associated with increased risk of relapse irrespective of the source of stem cells used.

Published
2014

198. Clinical features and outcome of SIL/TAL1-positive T-cell acute lymphoblastic leukemia in children and adolescents: a 10-year experience of the AIEOP group

Author

D'Angio, M., primary, Valsecchi, M. G., additional, Testi, A. M., additional, Conter, V., additional, Nunes, V., additional, Parasole, R., additional, Colombini, A., additional, Santoro, N., additional, Varotto, S., additional, Caniglia, M., additional, Silvestri, D., additional, Consarino, C., additional, Levati, L., additional, Magrin, E., additional, Locatelli, F., additional, Basso, G., additional, Foa, R., additional, Biondi, A., additional, and Cazzaniga, G., additional

Published
2014
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