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• W2014766273 abstract "Acute promyelocytic leukaemia (APL) is characterized by the PML-RARA fusion gene, arising from t(15;17)(q21;q22) translocation. PML-RARA is a specific molecular marker for APL and an important determinant for the effective induction of differentiation by all-trans retinoic acid (ATRA) (Grignani et al, 1994). We report a novel fusion gene, GTF2I-RARA, in a variant APL with cryptic t(7;17)(q11;q21), which manifested insensitivity to ATRA and conventional chemotherapy. The patient, a previously healthy 35-year-old male, presented with a 3-month history of fatigue and skin ecchymosis for 10 d. Laboratory investigations showed: haemoglobin level, 61 g/l; platelet count, 12 × 109/l; leucocyte count, 53·7 × 109/l, including 81% abnormal promyelocytes. Coagulopathy was present. A bone marrow (BM) aspirate showed 90% hypergranular promyelocytes with strong myeloperoxidase positivity (Fig 1A, B). The blast cells were positive for CD13, CD33, CD64 and negative for CD34, HLA-DR, CD7, CD14 and CD19 by flow cytometry. Reverse transcription polymerase chain reaction (RT-PCR) analysis of the BM was negative for PML-RARA, ZBTB16-RARA and NPM1-RARA (Table S1). FLT3 internal tandem duplication mutation was not found. Karyotype analysis showed 46,XY,del(7)(q22)[20] (Fig 1C). Fluorescence in situ hybridization (FISH) confirmed the deletion of 7q (Fig 1D) and detected split RARA signals without PML involvement (Fig 1E). One split RARA signal was located on the truncated long arm of chromosome 7 (Fig 1F). The diagnosis of a variant APL was made. Hydroxycarbamide and low dose ATRA (25 mg/m2) were immediately initiated following the support with platelet and plasma infusions. Daunorubicin (45 mg/m2/d for 3 d) was added on the second day, and DA regimen (daunorubicin 45 mg/m2/d, days 1–3; cytarabine 100 mg/m2/d, days 1–7) was added to continuous ATRA on day 23. ATRA improved coagulopathy without morphological differentiation of leukaemia cells. Subsequently, two cycles of salvage treatment, intermediate dose cytarabine and IAH regimen (idarubicin 12 mg/m2/d, days 1–3; cytarabine 100 mg/m2/d, days 1–7; homoharringtonine 2 mg/m2/d, days 1–4), failed. Because of the refractoriness of the disease, arsenic trioxide (0·16 mg/kg/d) was tried in combination with ATRA (25 mg/m2). Unfortunately, the patient died of intracranial haemorrhage on day 146 without achieving remission. The combination of APL morphology and immunophenotype suggested the diagnosis of APL. However, the classic PML-RARA fusion transcript and the t(15q+;17p−) translocation were absent, indicating this case was atypical. FISH analysis revealed that one split RARA signal was inserted into the disrupted 7q region, documenting the presence of submicroscopic t(7;17)(q?;q21) translocation (Fig 1F). Adopting rapid 5′amplification of cDNA ends (5′-RACE) and RT-PCR, we identified GTF2I, the general transcription factor IIi, as the novel RARA partner (Fig 2A). GTF2I-RARA results from the fusion between exon 6 of GTF2I and exon 3 of RARA, and is predicted to encode a 599 amino acid protein (Fig 2B). No alternative splicing variant was found. The reciprocal RARA-GTF2I fusion transcript was not detected (Fig 2C). Mapped at 7q11·23, GTF2I is ubiquitously expressed and encodes a phosphoprotein with broad roles in transcription and signal transduction involving growth factor signalling, cell cycle regulation, and transforming growth factor, beta 1 (TGFB1) signalling (Roy, 2012). The primary structure of GTF2I characterizes six direct reiterated I-repeats, R1-R6, each containing a helix-loop-helix motif that is a protein-protein module (Cheriyath & Roy, 2001). The conserved N-terminal leucine zipper (LZ, amino acids 23–44) mediates homo- or heteromeric interaction (Fig 2B). In the GTF2I-RARA fusion protein, the first 195 amino acids of GTF2I, including the LZ and the first I-repeat (R1, 104-176), are retained (Fig 2B), providing the possibility of GTF2I-RARA dimerization or multimerization. It has been reported that RARA chimaeras acquire their oncogenic potential by forming homodimers (Sternsdorf et al, 2006). Indeed, our coimmunoprecipitation results confirmed the self-association of GTF2I-RARA (Fig 2D). Additionally, GTF2I-RARA heterodimerizes with GTF2I, suggesting that it may contribute to leukaemogenesis by dysregulating the GTF2I-mediated signalling pathway. Double-labelling immunofluorescence experiments showed the co-localization of FLAG-tagged GTF2I-RARA with either HA-tagged GTF2I-RARA or GTF2I, but not with RARA, consistent with coimmunoprecipitation data (Fig 2E). In GTF2I-RARA-expressing cells, two patterns of GTF2I-RARA localization were observed: diffuse nuclear distribution with a micropunctate pattern, and aggregation in the cytoplasm as macrogranules (Fig 2E, upper panel). This is clearly distinct from the microspeckled pattern reported for PML-RARA. Apart from PML-RARA, 8 other RARA fusion genes have been reported in a small number of APL cases. The corresponding RARA partners are ZBTB16, NPM1, NUMA1, STAT5B, PRKAR1A, FIP1L1, BCOR, and NABP1 (Redner, 2002; Won et al, 2013). All these chimaeras possess identical RARA sequences and mainly act as dominant negative regulators on RARA/RXR pathways. GTF2I-RARA shares a common RARA portion and negatively regulates the retinoic acid response element (RARE) on luciferase assays (Fig 2F). It has been reported that ZBTB16-RARA and STAT5B-RARA variants are resistant to ATRA (Redner, 2002; Strehl et al, 2013). The explanation for ATRA resistance was ascribed to aberrant recruitment of co-repressors by the ZBTB16 or STAT5B portion, which did not dissociate in response to pharmacological concentrations of ATRA (He et al, 1998; Alexander et al, 2002). Consistent with the patient's clinical resistance to ATRA, GTF2I-RARA responds poorly to retinoic acid, similar to ZBTB16-RARA on luciferase assays (Fig 1F). As a transcription regulator, the inhibitory role of GTF2I was mediated by its ability to recruit co-repressor complexes (Roy, 2012). It is possible that GTF2I-RARA contributes to ATRA resistance by recruiting corepressors through the N-terminal GTF2I portion. Although rare, t(7;17)(q11;q21) was reported in a chronic myeloid leukaemia (CML) patient after chemotherapy, radiotherapy and imatinib treatment (Bumm et al, 2003). However, the t(7;17)(q11;q21) clonality did not constitute a haematopoietic advantage and the patient did not manifest APL phenotypes. Whether the patient had GTF2I-RARA transcript or another RARA rearrangement was unknown. We think that t(7;17)(q11;q21) in the CML patient might be an secondary event and was not related to APL leukaemogenesis, while GTF2I-RARA is an initiating event and responsible for the pathogenesis of this variant APL. In summary, we identified a novel GTF2I-RARA fusion transcript in a case of variant APL with cryptic t(7;17)(q11;q21) translocation. It represents a new subtype of APL that is resistant to retinoic acid differentiation induction therapy. Further studies are required to elucidate the pathogenesis of GTF2I-RARA APL. Supplementary data, including Supplementary Methods (Data S1) and Table S1, is available at British Journal of Haematology's website. This work was supported in part by Scientific Research Programme for Public Interests from the Health Ministry of China (project No. 201202017), a Clinical Research Programme from the Health Ministry of China (key project 2012-2014), and Project ‘Famous Clinical Doctors in Xiang-Ya Medical College of Central South University’ (2012-2014). G.S.Z diagnosed the case, designed and performed research, analysed data and wrote the paper; J.L performed research, collected and analysed data and wrote the paper; Y.Z finished parts of experiments; L.X performed cytogenetic and flow cytometric analysis; H.Y.Z provided clinical care and data collection; S.F.L was partly involved in experimental studies; L.H.B performed morphological analysis; G.B.Z contributed some study suggestions and reviewed the manuscript. All authors gave their final approval of the manuscript. The authors declare no conflict of interests. Data S1. Methods. Table S1. Hematological malignancies related fusion genes tested in our patient. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2014766273 title "<i>GTF2I-RARA</i>is a novel fusion transcript in a t(7;17) variant of acute promyelocytic leukaemia with clinical resistance to retinoic acid" @default.
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