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D Cilloni, F Messa,
V Rosso,
F Arruga,
I Defilippi,
S Carturan,
R Catalano,
M Pautasso,
C Panuzzo,
P Nicoli,
E Messa,
A Morotti,
I Iacobucci,
G Martinelli,
E Bracco,
G Saglio
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2010; · 8.30 Impact Factor
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D Cilloni,
S Carturan,
C Maffè, F Messa,
F Arruga,
E Messa,
M Pradotto,
M Pautasso,
C Zanone,
P Fornaciari,
I Defilippi,
A Rotolo,
E Greco,
I Iacobucci,
G Martinelli,
F Lo-Coco,
E Bracco,
G Saglio
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2010; · 8.30 Impact Factor
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I Iacobucci,
A Lonetti, F Messa,
A Ferrari,
D Cilloni,
S Soverini,
F Paoloni,
F Arruga,
E Ottaviani,
S Chiaretti, [......],
A Vitale,
F Pane,
P P Piccaluga,
S Paolini,
G Berton,
A Baruzzi,
G Saglio,
M Baccarani,
R Foà,
G Martinelli
[show abstract]
[hide abstract]
ABSTRACT: The main reason for the unfavorable clinical outcome of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR-ABL1-positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR-ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AIDDeltaE4a, with a 30-bp deletion of exon 4; AIDDeltaE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDDeltaE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-DeltaE4a and AID-DeltaE3E4 variants, whereas the C-terminal-truncated AID-DeltaE4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR-ABL1-positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2009; 24(1):66-73. · 8.30 Impact Factor
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I. Iacobucci,
C. T. Storlazzi,
D. Cilloni,
A. Lonetti,
E. Ottaviani,
S. Soverini,
A. Astolfi,
S. Chiaretti,
A. Vitale, F. Messa, [......],
S. Colarossi,
M. Vignetti,
P. P. Piccaluga,
S. Paolini,
D. Russo,
F. Pane,
G. Saglio,
M. Baccarani,
R. Foa,
G. Martinelli
[show abstract]
[hide abstract]
ABSTRACT: The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukemia (ALL) with the worst clinical prognosis. To identify oncogenic lesions that combine with BCR-ABL1 to cause ALL, we used Affymetrix Genome-Wide Human SNP arrays (250K NspI and SNP 6.0), fluorescence in situ hybridization, and genomic polymerase chain reaction to study 106 cases of adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was a focal deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros and was identified in 80 (75%) of 106 patients. Different patterns of deletions occurred, but the most frequent were those characterized by a loss of exons 4 through 7 (Delta4-7) and by removal of exons 2 through 7 (Delta2-7). A variable number of nucleotides (patient specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of the Delta4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localization and oncogenic activity, whereas the Delta2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion also was identified in the progression of chronic myeloid leukemia to lymphoid blast crisis (66%) but never in myeloid blast crisis or chronic-phase chronic myeloid leukemia or in patients with acute myeloid leukemia. Known DNA sequences and structural features were mapped along the breakpoint cluster regions, including heptamer recombination signal sequences recognized by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAG-mediated recombination.
Blood 01/2009; 114(10):2159-67. · 9.90 Impact Factor
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I. Iacobucci,
C. T. Storlazzi,
D. Cilloni,
A. Lonetti,
E. Ottaviani,
S. Soverini,
A. Astolfi,
S. Chiaretti,
A. Vitale, F. Messa, [......],
S. Colarossi,
M. Vignetti,
P. P. Piccaluga,
S. Paolini,
D. Russo,
F. Pane,
G. Saglio,
M. Baccarani,
R. Foa,
G. Martinelli
[show abstract]
[hide abstract]
ABSTRACT: The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukemia (ALL) with the worst clinical prognosis. To identify oncogenic lesions that combine with BCR-ABL1 to cause ALL, we used Affymetrix Genome-Wide Human SNP arrays (250K NspI and SNP 6.0), fluorescence in situ hybridization, and genomic polymerase chain reaction to study 106 cases of adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was a focal deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros and was identified in 80 (75%) of 106 patients. Different patterns of deletions occurred, but the most frequent were those characterized by a loss of exons 4 through 7 (Delta4-7) and by removal of exons 2 through 7 (Delta2-7). A variable number of nucleotides (patient specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of the Delta4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localization and oncogenic activity, whereas the Delta2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion also was identified in the progression of chronic myeloid leukemia to lymphoid blast crisis (66%) but never in myeloid blast crisis or chronic-phase chronic myeloid leukemia or in patients with acute myeloid leukemia. Known DNA sequences and structural features were mapped along the breakpoint cluster regions, including heptamer recombination signal sequences recognized by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAG-mediated recombination.
Blood 01/2009; 114(10):2159-67. · 9.90 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Transfusion-induced iron overload is a frequent problem that clinicians have to face in the treatment of patients affected by both myelodysplastic syndrome (MDS) and primary myelofibrosis (PMF). Different options are currently available for chelation therapy, e.g. oral once-daily administration of the iron chelator deferasirox. In 3 patients with MDS and 1 patient with PMF, deferasirox therapy resulted in an improvement in the hemoglobin level and a reduction in transfusion dependence. Our data open new insights regarding the benefit of iron chelation therapy not only for transfusional iron overload of myelodysplastic and myelofibrotic patients but also for the increase in hemoglobin levels. The biological mechanism of action of deferasirox, an effect which is not shared by other iron chelators, is still obscure and requires further investigations.
Acta Haematologica 11/2008; 120(2):70-4. · 1.35 Impact Factor
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D Cilloni, F Messa,
V Rosso,
F Arruga,
I Defilippi,
S Carturan,
R Catalano,
M Pautasso,
C Panuzzo,
P Nicoli,
E Messa,
A Morotti,
I Iacobucci,
G Martinelli,
E Bracco,
G Saglio
[show abstract]
[hide abstract]
ABSTRACT: Mutations in nucleophosmin (NPM) exon 12 and the resulting delocalization of NPM into the cytoplasm are the most specific and frequent cellular events in acute myeloid leukemia patients (AML) with normal karyotype. Cytoplasmatic NPM (NPMc+) is associated with responsiveness to chemotherapy and better prognosis. The activation of nuclear factor-kappaB (NF-kappaB) has been demonstrated to occur in a subset of AML patients and is thought to induce resistance to many chemotherapeutical agents. In this study, we demonstrate the increased in vitro sensitivity of NPMc+ cells to chemotherapeutical agents and their reduced NF-kappaB activity. Furthermore, we provide evidence of the interaction between NPMc+ and NF-kappaB in the cytoplasm, resulting in the sequestration and inactivation of NF-kappaB. The cytosolic localization and consequent inactivation of NF-kappaB justifies the reduced NF-kappaB DNA-binding activity observed in NPMc+ patients. These data, taken together, may provide a possible explanation for the increased rate of chemosensitivity observed among the NPMc+ patients.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2008; 22(6):1234-40. · 8.30 Impact Factor
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D Cilloni, F Messa,
G Martinelli,
E Gottardi,
F Arruga,
I Defilippi,
S Carturan,
E Messa,
M Fava,
E Giugliano, [......],
R Catalano,
S Merante,
P Nicoli,
M Rondoni,
E Ottaviani,
S Soverini,
M Tiribelli,
F Pane,
M Baccarani,
G Saglio
[show abstract]
[hide abstract]
ABSTRACT: Idiopathic hypereosinophilic syndromes (HES) comprise a spectrum of indolent to aggressive diseases characterized by persistent hypereosinophilia. Hypereosinophilia can result from the presence of a defect in the hematopoietic stem cell giving rise to eosinophilia, it can be present in many myeloproliferative disorders or alternatively it may be a reactive form, secondary to many clinical conditions. The hybrid gene FIP1L1-PDGRFalpha was identified in a subset of patients presenting with HES or chronic eosinophilic leukemia (CEL). In spite of this, the majority of HES patients do not present detectable molecular lesions and for many of them the diagnosis is based on exclusion criteria and sometimes it remains doubt. In this study we explored the possibility to distinguish between HES/CEL and reactive hypereosinophilia based on WT1 transcript amount. For this purpose, 312 patients with hypereosinophilia were characterized at the molecular and cytogenetic level and analyzed for WT1 expression at diagnosis and during follow-up. This study clearly demonstrates that WT1 quantitative assessment allows to discriminate between HES/CEL and reactive eosinophilia and represents a useful tool for disease monitoring especially in the patients lacking a marker of clonality.
Leukemia 08/2007; 21(7):1442-50. · 9.56 Impact Factor
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A Morotti,
G Parvis,
D Cilloni,
U Familiari,
M Pautasso,
M Bosa, F Messa,
F Arruga,
I Defilippi,
R Catalano,
V Rosso,
S Carturan,
E Bracco,
A Guerrasio,
G Saglio
Leukemia 07/2007; 21(6):1305-6. · 9.56 Impact Factor
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A Morotti,
D Cilloni,
M Pautasso, F Messa,
F Arruga,
I Defilippi,
S Carturan,
R Catalano,
V Rosso,
A Chiarenza,
R Taulli,
E Bracco,
G Rege-Cambrin,
E Gottardi,
G Saglio
[show abstract]
[hide abstract]
ABSTRACT: NF-kB is a transcription factor that mediates antiapoptotic signals in several cancer cell lines. Here we have demonstrated that the cytotoxic drug, Etoposide, activates NF-kB in K562, a chronic myeloid leukemia blast crisis cell line. Treatment with the NF-kB inhibitors MG-132, Bay11-7082, and Resveratrol impedes Etoposide-induced NF-kB activation, rendering K562 sensitive to Etoposide-induced apoptosis. Stable expression of mutant form of IkB-alpha, which retains NF-kB inactive in the cytoplasm of cells, confirmed the data obtained with molecular inhibitors. Both inhibitors and stable expression of SR-IkB are associated with down-modulation of the antiapoptotic protein Bcl-xL, suggesting that the survival pathway activated by Etoposide involves NF-kB-mediated Bcl-xL expression.
American Journal of Hematology 01/2007; 81(12):938-45. · 4.67 Impact Factor
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D Cilloni, F Messa,
F Arruga,
I Defilippi,
A Morotti,
E Messa,
S Carturan,
E Giugliano,
M Pautasso,
E Bracco,
V Rosso,
A Sen,
G Martinelli,
M Baccarani,
G Saglio
[show abstract]
[hide abstract]
ABSTRACT: Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-kappaB/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Rel-blocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-kappaB activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.
Leukemia 02/2006; 20(1):61-7. · 9.56 Impact Factor
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D Cilloni,
E Gottardi,
D De Micheli,
A Serra,
G Volpe, F Messa,
G Rege-Cambrin,
A Guerrasio,
M Divona,
F Lo Coco,
G Saglio
[show abstract]
[hide abstract]
ABSTRACT: In order to verify if quantitative assessment of the WT1 transcript amount by the real time quantitative PCR (RQ-PCR) can be used as a marker for minimal residual disease detection, the WT1 transcript amount was determined in BM and PB samples of patients with myeloid and lymphoid acute leukemia, in normal controls, in regenerating bone marrow samples and in purified CD34-positive cells from normal subjects. In 10 patients bearing a fusion gene transcript suitable for minimal residual disease quantitative assessment, we performed a simultaneous analysis of the WT1 and of the fusion-gene transcript at sequential time intervals during follow-up. Sequential WT1 analysis was also performed in five AML patients lacking additional molecular markers. The data obtained show that normal and regenerating BM samples and purified CD34-positive cells consistently express minimal amounts of WT1 transcript and that this is extremely low and frequently undetectable in normal PB. By contrast, high levels of WT1 expression are present in the BM and PB samples of all acute leukemia (AL) cases at diagnosis. The WT1 levels during follow-up were found to follow the pattern of the other molecular markers (fusion gene transcripts) used for MRD monitoring and increased WT1expression in the BM and/or PB during follow-up of AL patients was always found to be predictive of an impending hematological relapse.
Leukemia 11/2002; 16(10):2115-21. · 9.56 Impact Factor
