TY - JOUR A1 - Rouhigharabaei, Leila A1 - Ferreiro, Julio Finalet A1 - Tousseyn, Thomas A1 - van der Krogt, Jo-Anne A1 - Put, Natalie A1 - Haralambieva, Eugenia A1 - Graux, Carlos A1 - Maes, Brigitte A1 - Vicente, Carmen A1 - Vandenberghe, Peter A1 - Cools, Jan A1 - Wlodarska, Iwona T1 - Non-IG Aberrations of FOXP1 in B-Cell Malignancies Lead to an Aberrant Expression of N-Truncated Isoforms of FOXP1 JF - PLOS ONE N2 - The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through chromosomal translocations involving either immunoglobulin heavy chain (IGH) locus or non-IG sequences. The former translocation, t(3; 14)(p13; q32), results in dysregulated expression of FOXP1 juxtaposed with strong regulatory elements of IGH. Thus far, molecular consequences of rare non-IG aberrations of FOXP1 remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3; 14)(p13; q32)/IGH-FOXP1 and FOXP1-expressing lymphomas with no apparent structural aberrations of the gene. Our study revealed that non-IG rearrangements of FOXP1 are usually acquired during clinical course of various lymphoma subtypes, including diffuse large B cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukemia, and correlate with a poor prognosis. Importantly, these aberrations constantly target the coding region of FOXP1, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). The non-IG rearrangements of FOXP1, however, do not generate functional chimeric genes but commonly disrupt the full-length FOXP1 transcript leading to an aberrant expression of N-truncated FOXP1 isoforms (FOXP1NT), as shown by QRT-PCR and Western blot analysis. In contrast, t(3; 14)(p13; q32)/IGH-FOXP1 affects the 59 untranslated region of FOXP1 and results in overexpress the full-length FOXP1 protein (FOXP1FL). RNA-sequencing of a few lymphoma cases expressing FOXP1NT and FOXP1FL detected neither FOXP1-related fusions nor FOXP1 mutations. Further bioinformatic analysis of RNA-sequencing data retrieved a set of genes, which may comprise direct or non-direct targets of FOXP1NT, potentially implicated in disease progression. In summary, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. We hypothesize that the primary t(3; 14)(p13; q32)/IGH-FOXP1 activates expression of the FOXP1FL protein with potent oncogenic activity, whereas the secondary non-IG rearrangements of FOXP1 promote expression of the FOXP1NT proteins, likely driving progression of disease. KW - lymphoid-tissue lymphomas KW - acute lymphoblastic leukemia KW - transcription factor FOXP1 KW - cardiomyocyte proliferation KW - chromosomal aberration KW - prostate cancer KW - down regulation KW - poor prognosis KW - malt lymphoma KW - gene Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117679 SN - 1932-6203 VL - 9 IS - 1 ER - TY - JOUR A1 - Deak, Dalma A1 - Pop, Cristina A1 - Zimta, Alina-Andreea A1 - Jurj, Ancuta A1 - Ghiaur, Alexandra A1 - Pasca, Sergiu A1 - Teodorescu, Patric A1 - Dascalescu, Angela A1 - Antohe, Ion A1 - Ionescu, Bogdan A1 - Constantinescu, Catalin A1 - Onaciu, Anca A1 - Munteanu, Raluca A1 - Berindan-Neagoe, Ioana A1 - Petrushev, Bobe A1 - Turcas, Cristina A1 - Iluta, Sabina A1 - Selicean, Cristina A1 - Zdrenghea, Mihnea A1 - Tanase, Alina A1 - Danaila, Catalin A1 - Colita, Anca A1 - Colita, Andrei A1 - Dima, Delia A1 - Coriu, Daniel A1 - Einsele, Hermann A1 - Tomuleasa, Ciprian T1 - Let’s Talk About BiTEs and Other Drugs in the Real-Life Setting for B-Cell Acute Lymphoblastic Leukemia JF - Frontiers in Immunology N2 - Background: Therapy for acute lymphoblastic leukemia (ALL) are currently initially efficient, but even if a high percentage of patients have an initial complete remission (CR), most of them relapse. Recent data shows that immunotherapy with either bispecific T-cell engagers (BiTEs) of chimeric antigen receptor (CAR) T cells can eliminate residual chemotherapy-resistant B-ALL cells. Objective: The objective of the manuscript is to present improvements in the clinical outcome for chemotherapy-resistant ALL in the real-life setting, by describing Romania's experience with bispecific antibodies for B-cell ALL. Methods: We present the role of novel therapies for relapsed B-cell ALL, including the drugs under investigation in phase I-III clinical trials, as a potential bridge to transplant. Blinatumomab is presented in a critical review, presenting both the advantages of this drug, as well as its limitations. Results: Bispecific antibodies are discussed, describing the clinical trials that resulted in its approval by the FDA and EMA. The real-life setting for relapsed B-cell ALL is described and we present the patients treated with blinatumomab in Romania. Conclusion: In the current manuscript, we present blinatumomab as a therapeutic alternative in the bridge-to-transplant setting for refractory or relapsed ALL, to gain a better understanding of the available therapies and evidence-based data for these patients in 2019. KW - blinatumoman KW - acute lymphoblastic leukemia KW - bridge-to-transplant KW - real life setting KW - bispecific antobodies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193921 SN - 1664-3224 VL - 10 IS - 2856 ER -