A novel fusion of SQSTM1 and FGFR1 in a patient with acute myelomonocytic leukemia with t(5;8)(q35;p11) translocation
Authors: Y Nakamura, Y Ito, N Wakimoto, E Kakegawa, Y Uchida, M Bessho
Journal: Blood Cancer Journal (2014)

Hematological malignancies with FGFR1 abnormality (8p11 myeloproliferative syndrome; EMS) are rare atypical stem cell disorders characterized by eosinophilia, T-cell proliferation and progression to acute myeloid leukemia. 1,2 In EMS, fibroblast growth factor receptor 1 (FGFR1) gene at 8p11 is disrupted by chromosomal translocation, resulting in the formation of chimeric products with various partner genes.To date, 13 FGFR1 partners have been identified: ZMYM2 (ZNF198) at 13q12; CNTR at 9q33; FGFR1OP at 6q27; BCR at 22q11; HERVK at 19p13.3;FGFR1OP2 at 12p11; TRIM24 (TIF1) at 7q34; CPSF6 at 12q15; MYO18A at 17q23; LRRFIP1 at 2q37; CUX1 at 7q34; TPR at 1q25; and RANBP2/NUP358 at 2q12. [2]3][4][5] In all reported cases in which chimeric transcripts were cloned, N-terminal portion of the predicted fusion protein is composed of a partner gene with a dimerization domain, which may induce the constitutive activation of FGFR1 tyrosine kinase in the C-terminal portion, leading to the cellular transformation. 2 Here, we report the identification of sequestosome 1 (SQSTM1) gene at 5q35 as a novel fusion partner of the FGFR1 in a patient with acute myelomonocytic leukemia presenting 8p11 chromosomal abnormality.A 76-year-old man was referred to our hospital for anemia with hemoglobin level of 5.0 g/dl.The white blood cell count was 4.1 × 10 9 cells/l with 11% blasts, 1% eosinophils, 29% neutrophils and 30% monocytes, Bone marrow (BM) was hypercellular with 43% blasts and 17% monocytes.Dysplastic changes were observed in peripheral neutrophils and BM megakaryocytes.Immunphenotyping revealed that leukemic cells were positive for CD13, CD33, CD34 and HLA-DR and negative for other myeloid and lymphoid markers.He was diagnosed as acute myelomonocytic leukemia and received blood transfusion therapy for anemia, but chemotherapy was not done because of poor performance status.He died of progressive disease 15 months after the diagnosis.Chromosome analysis of the BM cells showed the karyotype as 46,XY,t(5;8)(q35;p11) (20/20 cells) (Figure 1a).To characterize the 8p11 translocation, Southern blot analysis of DNA from the patient's peripheral leukemic cells was performed using a genomic probe containing FGFR1 exon 9 and 10, as chromosomal breaks occur within intron 8 in most cases with EMS.Abnormal bands were observed in sample with BamHI or HindIII digestion (Figure 1b), confirming that FGFR1 was rearranged by the translocation.To determine the FGFR1 partner gene, we searched for a FGFR1 chimeric transcript by 5′-rapid amplification of cDNA end (RACE) method using 5'-Full RACE core set (Takara Bio, Otsu, Japan).Total RNA was extracted from the leukemic cells and the first cDNA strand was synthesized with phosphorylated primer in FGFR1 exon 12 (5′-GCCAGATACTCCATGCCTCG-3′) by reverse transcription.After ligation, cDNA was amplified by PCR with FGFR1-10R1 (5′-ACACCACCTGCCCAAAGCAGC-3′) and FGFR1-10F1 (5′-AGGCT ATCGGGCTGGACAAGG-3′) primers in exon 10.The PCR product was further amplified with FGFR1-10R2 (5′-CAGGGGTTTGCCTAA GACCAG-3′) and FGFR1-10F2 (5′-CGTGTGACCAAAGTGGCTGTG-3′)