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LRRFIP1, a New FGFR1 Partner Gene Associated with 8P11 Myeloproliferative Syndrome

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LRRFIP1, a New FGFR1 Partner Gene Associated with 8P11 Myeloproliferative Syndrome Letters to the Editor 1359 LRRFIP1, a new FGFR1 partner gene associated with 8p11 myeloproliferative syndrome Leukemia (2009) 23, 1359–1361; doi:10.1038/leu.2009.79; lymphocytes revealed a normal karyotype, confirming that the published online 16 April 2009 t(2;8)(q37;p11) translocation was acquired, and suggesting the diagnosis of EMS. A fluorescence in situ hybridization experiment with BAC RP11-333B24 as a probe spanning the FGFR1 locus Hematological malignancies associated with FGFR1 rearrange- confirmed the expected gene rearrangement (Figure 1b). To ments (8p11-chromosome eighth-myeloproliferative syndrome identify the derivative chromosome der(2) breakpoint, fluorescence (EMS) are rare atypical chronic myeloproliferative disorders that in situ hybridization experiments were performed with a series of are in most cases associated with eosinophilia and T-cell BAC clones covering chromosomal band 2q37. A split signal was proliferation. Clinically, EMS is an aggressive disease with a observed for the BAC RP11-497D24 indicating that it contained short chronic phase leading to rapid transformation into acute the chromosome 2 breakpoint (Figure 1b). Furthermore, retro- myeloid leukemia. The only effective treatment to date is spective analysis by fluorescence in situ hybridization using BACs allogenic stem cell transplantation. The genetic hallmark of this RP11-333B24 and RP11-497D24 on bone marrow smears pathology is a recurrent chromosomal 8p11 rearrangement that performed in 2002 revealed two normal signals for each BAC fuses the tyrosine kinase domain of the fibroblast growth factor (data not shown), indicating that the t(2;8) translocation was a receptor 1 gene (FGFR1) to different gene partners. To date, nine secondary event acquired at the time of transformation into acute FGFR1 partners have been identified in patients with EMS: myeloid leukemia. ZMYM2/ZNF198 at 13q12, FGFR1OP/FOP at 6q27, CEP110/ The 2q37 BAC RP11-497D24 harbors two genes in the same CEP1 at 9q33, BCR at 22q11, FGFR1OP2 at 12p11, TRIM24/ orientation as FGFR1 (50 centromereF30 telomere): LRRFIP1 TIF1 at 7q34, MYO18A at 17q23, CPSF6 at 12q15 and a human and RAMP1. As all FGFR1 fusion genes reported to date share endogenous retroviral sequence, HERV-K at 19q13.3. Here, we the feature of contributing their 50 portion to the fusion joined by report the identification of a tenth FGFR1 partner gene in a case the 30 of FGFR1, and because the LRRFIP1 50 part was coding for of EMS associated with a t(2;8)(q37;p11) translocation. an N-terminal coiled-coil domain, as in many FGFR1 partners, The patient, an 82-year-old man, was referred to our we hypothesized that LRRFIP1 was a more likely candidate department in May 2002 for pancytopenia with hemoglobin partner for an in-frame fusion with FGFR1. Thus, we performed level of 10 g per 100 ml, a white blood cell count of 2.4 Â 109/l reverse transcription-PCR with specific primers designed to and a platelet count of 40 Â 109/l. Bone marrow aspiration amplify a putative LRRFIP1–FGFR1 fusion transcript. Total RNA showed a refractory anemia with an excess of blasts (15%). was extracted from patient bone marrow cells and reverse Cytogenetical analysis was not performed at that time. Between transcribed using random hexamers and Superscript II reverse 2002 and 2007, the white blood cell count remained stable and transcriptase (Invitrogen, Carlsbad, CA, USA). We obtained the patient was occasionally treated with red blood cell specific amplification of the putative fusion transcript from transfusion depending on the hemoglobin levels (see Table 1 cDNA with the following design: as all FGFR1 fusions described for evolution of blood counts). In September 2007, the white show a genomic breakpoint close to exon 9, we performed blood cell count increased to 20 Â 109/l with 10% eosinophils, reverse transcription-PCR using several forward primers located 2–4% myelocytes and metamyelocytes, and 8% circulating in the LRRFIP1 reference sequence (NM_004735.2) and one blasts. Bone marrow aspiration was hypocellular with moderate reverse primer located in exon 10 of FGFR1 (FGFR1ex10: dysgranulopoiesis and 15% blasts. The presence of dacryocytes 50-ACAGCCACTTTGGTCACACGGT-30). A specific fragment on blood smears suggested some degree of myelofibrosis. In was detected using a forward primer located in exon 4 of May 2008, a new blood count showed a decrease in LRRFIP1 (LRRex4: 50-AGACGAGCGCATGTCAGTGGGTAGT- hemoglobin levels (8 g per 100 ml) and a stable white blood 30), which was not amplified in U937 control cells (Figure 2a, cell count with an increase in blasts (42%), attesting to the lanes 1 and 4). Sequence analysis of the PCR product revealed transformation into acute myeloid leukemia. Supportive care the in-frame fusion of LRRFIP1 exon 9 with FGFR1 exon 9 with red blood cell transfusions permitted outpatient care at first, (Figure 2b). As public sequence databases contain an alternative but the patient died 1 year later. transcript for LRRFIP1 that has coding potential for a highly The karyotype, as performed on bone marrow cells in September divergent protein (ENST00000308482, at the Ensembl Genome 2007, was interpreted as follows: 46,XY,t(2;8)(q37;p11)[20] database), we performed reverse transcription-PCR using a (Figure 1a). Conventional cytogenetic analysis on patient blood primer that is located in this alternative sequence but is absent Table 1 Patient blood counts during disease progress Period May 02–April 07 September 07–February 08 May 08–October 08 Disease phase RAEB Accelerating phase AML WBC count, Â 109/l 3.2 (1.7–7.1) 16.5 (11.2–20.1) 8.3 (1.5–12.2) Eosinophils, % of WBC 2.9 (1–9) 12 (10–14) 2.6 (0–5) Circulating blasts, % of WBC 3.3 (1–12) 6.7 (4–8) 57 (42–68) Hemoglobin, g per 100 ml 8.6 (6.8–11.5) 11.7 (10.9–12.1) 9.0 (7.5–11.7) Platelets count, Â 109/l 30 (8–73) 104 (54–139) 22 (15–29) Abbreviations: AML, acute myeloid leukemia; RAEB, refractory anemia with excess of blasts; WBC, white blood cells. All values are mean values (range). Leukemia Letters to the Editor 1360 chr2 der2 chr8 der8 Figure 1 Cytogenetic analysis of patient bone marrow cells. (a) Partial karyotype showing the derivative chromosomes 2 and 8. (b) Fluorescence in situ hybridization using the RP11-333B24 BAC spanning the FGFR1 locus (left) and the RP11-497D24 BAC (right). RP11-333B24 hybridization shows one normal signal on a chromosome 8 (arrow), one signal on chromosome der2 (arrow head) and one signal on chromosome der 8 (asterisk). RP11-497D24 hybridization gives one normal signal on a chromosome 2 (arrow), one signal on chromosome der2 (arrow head) and one signal on chromosome der8 (asterisk). ARNT patient U937 kb U937 123456 patient 1.6 0.7 0.3 0.15 LRRFIP1 exon 9 FGFR1 exon 9 GTCAAGGAGGCCCTGAAGCAAAGAGAGGAAATGCTCGAGGTGTCTGCTGACTCCAGTGCATCCATGAACTCTGGGGTT V K E A L K Q R E E M L E V S A D S S A S M N S G V FGFR1 exon 8 LRRFIP1 exon 10 AAGCTGGCCAAGAGCATCCCTCTGCGCAGACAGGTAACAAAACATGGAATAATCCTAAATTCAGAAATAGCTACCAATGGA K L A K S I P L R R Q V T K H G I I L N S E I A T N G Figure 2 Molecular analysis of the LRRFIP1–FGFR1 fusion. (a) Lanes 1 and 4: specific reverse transcription (RT)-PCR amplification of an LRRFIP1– FGFR1 fusion transcript from a patient sample. Lanes 2 and 5: no amplification was obtained with primer localized in the alternative transcript of LRRFIP1. Lanes 3 and 6: specific amplification of the reciprocal FGFR1–LRRFIP1 fusion transcript in patient cells. RT-PCR using primers for ARNT serve as control. (b) Partial sequence of the LRRFIP1-FGFR1 fusion transcript. The exon 9 of FGFR1 is fused to LRRFIP1 exon 9 (bold). The amino- acid translation spanning the fusion is shown under the sequence. (c) Partial sequence of the reciprocal LRRFIP1–FGFR1 fusion cDNA with its amino-acid translation. from the LRRFIP1 reference sequence (L-ex6: 50-TGAGGTCG CATCTATTGCA-30) and a reverse primer located in LRRFIP1 CAGCCTGACTTGGAGTAT-30). No reverse transcription-PCR exon 11 (50-TCACCTCCACTTCACTGGCTCT-30) (Figure 2a, lane product was amplified from this second reaction (Figure 2a, 3). This product was sequenced and confirmed to be the lanes 2 and 5), indicating that the LRRFIP1–FGFR1 fusion in-frame fusion of exon 8 of FGFR1 with exon 10 of LRRFIP1 transcript above may be the single specific transcript produced (Figure 2c). by the translocation. A reciprocal FGFR1–LRRFIP1 fusion LRRFIP1 (Leucine-rich repeat Flightless-Interacting Protein 1) transcript was also detected in patient cells using a forward gene (also known as GCF2 for GC-binding factor 2 or TRIP for primer located in FGFR1 exon 8 (50-TGTACCTGGAGATCAT- TAR RNA Interacting Protein) is thus the tenth FGFR1 gene Leukemia Letters to the Editor 1361 FGFR1 LRRFIP1 LRRFIP1- FGFR1 Ig-like domain Coiled -coil domain Transmembrane domain DNA-binding domain Tyrosine kinase domain Lysine-rich motif Figure 3 Schematic representation of FGFR1, LRRFIP1 and the predicted LRRFIP1–FGFR1 fusion protein. Relevant protein domains are shown. The breakpoints within proteins are indicated by arrows. partner. LRRFIP1 is ubiquitously expressed and encodes for a 1Service de Cytoge´ne´tique, Assistance Publique-Hoˆpitaux de protein found in the nuclear and cytoplasmic compartments. Paris, Necker-Enfants Malades Hospital, Paris, France; 2School of Medicine, Universite´ Paris Descartes, Paris, France; The LRRFIP1 protein has multiple and complex functions. In the 3 nucleus, it acts as a transcriptional repressor that decreases Service d’He´matologie Clinique, Assistance Publique- Hoˆpitaux de Paris, Necker-Enfants Malades Hospital, Paris, the expression of the epidermal growth factor receptor1 and of 2 France and the platelet-derived growth factor a-chain.
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