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2.
Hematol Oncol ; 32(1): 22-30, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23861036

ABSTRACT

Trisomy 12 (+12) is the third most frequent cytogenetic aberration in chronic lymphocytic leukaemia (CLL) retrievable both as the sole chromosomal abnormality or in association with additional alterations. NOTCH1 mutations are known to be more prevalent among +12 patients, whereas mutations of FBXW7, a gene involved in NOTCH1 degradation, that lead to the constitutional activation of NOTCH1 have not been investigated in this setting. We analyzed a unicentric cohort of 44 +12 patients with CLL for mutations of TP53, NOTCH1 and FBXW7 genes, and we correlated them with B-cell receptor (BCR) configurations. FBXW7, TP53 and NOTCH1 mutations were identified in 4.5%, 6.8% and 18.2% of patients, respectively. FBXW7 and NOTCH1 mutations appeared in a mutually exclusive fashion, suggesting that both aberrations might affect the same biological pathway. We found that 44.1% of +12 CLL patients had stereotyped B-cell receptors, which is significantly higher than that observed in patients with CLL and no +12 (27%, p = 0.01). Subsets #1, #8, #10, #28 and #59 were the most represented stereotyped patterns, and IGHV4-39*01 was the gene configuration most commonly used. There was a significantly higher risk for Richter's syndrome (RS) transformation in patients with NOTCH1 or FBXW7 mutations, with four of the seven (57%) patients developing RS and characterized at least by one of the two abnormalities. These observations suggest that, similarly to the aberrations of NOTCH1, FBXW7 gene mutations may also result in cell proliferation and evasion from apoptosis in patients with +12 CLL. Together with the extremely high frequency of stereotyped BCRs and RS transformation, these abnormalities appear to cluster in these CLL patients with additional chromosome 12, suggesting a connection with the prognosis of the disease.


Subject(s)
Chromosomes, Human, Pair 12 , DNA, Neoplasm/genetics , Gene Rearrangement, B-Lymphocyte , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Trisomy , Aged , Amino Acid Sequence , Animals , Cell Cycle Proteins/genetics , Cell Transformation, Neoplastic/genetics , Clone Cells/pathology , Conserved Sequence , DNA Mutational Analysis , Disease Progression , F-Box Proteins/genetics , F-Box-WD Repeat-Containing Protein 7 , Female , Gene Rearrangement, B-Lymphocyte, Heavy Chain , Genes, Immunoglobulin , Genes, p53 , Humans , In Situ Hybridization, Fluorescence , Interphase/genetics , Male , Middle Aged , Molecular Sequence Data , Neoplastic Stem Cells/pathology , Receptor, Notch1/genetics , Sequence Alignment , Sequence Homology, Amino Acid , Species Specificity , Syndrome , Ubiquitin-Protein Ligases/genetics
3.
Am J Hematol ; 88(4): 289-93, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23450436

ABSTRACT

Treatment of patients with B-cell chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to conventional treatments is particularly challenging. The combination of bendamustine and cytarabine has demonstrated distinct and synergistic mechanisms of action in preclinical studies on cell lines and primary tumor cells of several B-cell lymphomas, including 17p deleted or TP53 mutated CLL. The efficacy of rituximab (375 mg/m(2) , Day 1), plus bendamustine (70 mg/m(2) , days 1-2), and cytarabine (800 mg/m(2) , Day 1-3; R-BAC), every 28 days for up to four courses, was evaluated in a pilot trial enrolling 13 patients with very selected high-risk R/R CLL. All patients (median age 60 years, range 53-74) had symptomatic Binet stage B or C active disease requiring treatment, were characterized by adverse cytogenetics (17p deletion, 11q deletion, or both), unmutated immunoglobulin heavy-chain variable region, and were heavily pretreated (1-5, median three previous lines). Overall, R-BAC was well tolerated with limited non-hematological toxicity. Major toxicities were transient Grade 3/4 neutropenia and thrombocytopenia in 84% and 85% of patients, respectively. Overall response rate (OR) was 84%, including complete and partial response in 38% and 46% of patients, respectively. Patients with 17p deletion had an OR of 78%. After a median follow-up of 17 months, median progression-free survival was 16 months while median overall survival (OS) was not reached (1-year OS: 75 ± 13%). R-BAC is an active regimen in R/R heavily pretreated high-risk patients with CLL, representing an option for the treatment of patients that are usually refractory to standard therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chromosome Aberrations , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 17 , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Aged , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Bendamustine Hydrochloride , Cytarabine/administration & dosage , Cytogenetic Analysis , Drug Administration Schedule , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Neoplasm Staging , Nitrogen Mustard Compounds/administration & dosage , Pilot Projects , Recurrence , Risk , Rituximab , Sequence Deletion , Survival Analysis
5.
Cancer Res ; 65(2): 587-95, 2005 Jan 15.
Article in English | MEDLINE | ID: mdl-15695403

ABSTRACT

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [(3)H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G(0)-G(1) together with a marked up-regulation of p27(Kip1) by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21(Cip1) inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27(Kip1) was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor alpha cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.


Subject(s)
CD40 Antigens/pharmacology , Interleukin-4/pharmacology , Lymphoma, Mantle-Cell/drug therapy , Tretinoin/pharmacology , Aged , CD40 Ligand/biosynthesis , Cell Cycle Proteins/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclin D1/metabolism , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase Inhibitor p21 , Cyclin-Dependent Kinase Inhibitor p27 , Cyclin-Dependent Kinases/metabolism , Female , Humans , Lymphoma, Mantle-Cell/metabolism , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors , Proto-Oncogene Proteins/metabolism , Receptors, Retinoic Acid/physiology , Tumor Suppressor Proteins/metabolism
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