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1.
Blood Cancer J ; 4: e249, 2014 Oct 10.
Article in English | MEDLINE | ID: mdl-25303368

ABSTRACT

Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients.


Subject(s)
Gene Expression Regulation, Neoplastic , Immunoglobulin Heavy Chains , Lymphoma, Follicular , Proto-Oncogene Proteins c-bcl-2 , Cell Line, Tumor , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 18/genetics , Female , Humans , Immunoglobulin Heavy Chains/biosynthesis , Immunoglobulin Heavy Chains/genetics , In Situ Hybridization, Fluorescence , Lymphoma, Follicular/genetics , Lymphoma, Follicular/metabolism , Lymphoma, Follicular/mortality , Lymphoma, Follicular/pathology , Male , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Translocation, Genetic
2.
Oncogene ; 31(43): 4599-608, 2012 Oct 25.
Article in English | MEDLINE | ID: mdl-22179831

ABSTRACT

Once stimulated, the epidermal growth factor receptor (EGFR) undergoes self-phosphorylation, which, on the one hand, instigates signaling cascades, and on the other hand, recruits CBL ubiquitin ligases, which mark EGFRs for degradation. Using RNA interference screens, we identified a deubiquitinating enzyme, Cezanne-1, that opposes receptor degradation and enhances EGFR signaling. These functions require the catalytic- and ubiquitin-binding domains of Cezanne-1, and they involve physical interactions and transphosphorylation of Cezanne-1 by EGFR. In line with the ability of Cezanne-1 to augment EGF-induced growth and migration signals, the enzyme is overexpressed in breast cancer. Congruently, the corresponding gene is amplified in approximately one third of mammary tumors, and high transcript levels predict an aggressive disease course. In conclusion, deubiquitination by Cezanne-1 curtails degradation of growth factor receptors, thereby promotes oncogenic growth signals.


Subject(s)
Endopeptidases/metabolism , ErbB Receptors/metabolism , Neoplasms/pathology , Catalysis , Disease Progression , Humans , Neoplasms/metabolism , Phosphorylation , RNA, Small Interfering , Ubiquitin/metabolism , Ubiquitination
3.
Ann Oncol ; 22(3): 712-717, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20810547

ABSTRACT

BACKGROUND: Intensification of chemoradiation for advanced head and neck squamous cell carcinoma (HNSCC) is unlikely due to toxicity. Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic profile with positive results in both combinations. Therefore, cetuximab could intensify chemoradiation without worsening toxicity. We conducted a phase II study of chemoradiation and cetuximab. PATIENTS AND METHODS: Eligible patients had stage III-IV M0 HNSCC. Treatment consisted of three cycles of cisplatin (20 mg/m(2)/day × 5 days) and fluorouracil (200 mg/m(2)/day × 5 days) rapidly alternated to three split courses of radiotherapy up to 70 Gy and concurrent weekly cetuximab. The primary end point of the study was complete response (CR) rate. Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS: Fourty-five patients were enrolled: median age was 56 years, 38 had stage IV disease and 40 nodal involvement. CR occurred in 32 patients (71%). PFS and OS was 21+ months and 32.6+, respectively. Acute grade 3-4 toxic effects were in the expected range, but grade 3 radiodermatitis occurred in 33 patients. CONCLUSIONS: The combination of cetuximab, cisplatin, fluorouracil and radiotherapy leads to a very high proportion of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy. The only unexpected toxicity was skin toxicity: grade 3 radiodermatitis occurred in 73% of the patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Squamous Cell/mortality , Cetuximab , Cisplatin/administration & dosage , Combined Modality Therapy , Female , Head and Neck Neoplasms/mortality , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Radiodermatitis/chemically induced , Treatment Outcome , Young Adult
5.
Leukemia ; 17(11): 2107-12, 2003 Nov.
Article in English | MEDLINE | ID: mdl-12931223

ABSTRACT

Conventional cytogenetics (CC) at clinical diagnosis shows a normal karyotype in 40-60% of de novo myelodysplastic syndromes (MDSs). Fluorescence in situ hybridization (FISH) might detect occult aberrations in these patients. Therefore, we have used FISH to check 57 MDS patients who were karyo-typically normal on CC. At clinical diagnosis, FISH revealed a clonal abnormality in 18-28% interphase cells from nine patients, five of whom also presented the same defect on metaphase FISH. In five out of nine patients, the occult defect effected a change in the international prognostic scoring system (IPSS). An abnormal FISH pattern was significantly correlated with marrow blast cell percentage (P<10(-3)) and IPSS (P<10(-3)). Patients with an occult abnormality showed an overall survival and event-free survival significantly inferior in comparison to those of patients with normal FISH (P<10(-3), P<10(-3)). Death and AML progression were 15- and eight-fold more frequent in FISH abnormal patients. In conclusion, occult defects (1) are revealed in about 15% of CC normal MDS patients, (2) are overlooked by CC either because of the poor quality of metaphases or their submicroscopic nature, (3) are clinically relevant as they may cause a change in the IPSS category and may identify a fraction of CC normal patients with an unfavorable clinical outcome.


Subject(s)
Chromosome Aberrations , Chromosome Mapping , In Situ Hybridization, Fluorescence , Myelodysplastic Syndromes/genetics , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Karyotyping , Male , Middle Aged , Myelodysplastic Syndromes/therapy , Prognosis , Proportional Hazards Models , Reference Values , Treatment Outcome
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