Identification of four new translocations involving FGFR1 in myeloid disorders

Abstract

The 8p11 myeloproliferative syndrome (EMS) is associated with three translocations, t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), that fuse unrelated genes (ZNF198, CEP110, and FOP, respectively) to the entire tyrosine kinase domain of FGFR1. In all cases thus far examined (n = 10), the t(8;13) results in an identical mRNA fusion between ZNF198 exon 17 and FGFR1 exon 9. To determine if consistent fusions are also seen in the variant translocations, we performed RT-PCR on four cases and sequenced the products. For two patients with a t(8;9), we found that CEP110 exon 15 was fused to FGFR1 exon 9. For two patients with a t(6;8), we found that FOP exon 5 (n = 1) or exon 7 (n = 1) was fused to FGFR1 exon 9. To determine if FGFR1 might be involved in other myeloid disorders with translocations of 8p, we developed a two-color FISH assay using two differentially labeled PAC clones that flank FGFR1. Disruption of this gene was indicated in a patient with a t(8;17)(p11;q25) and Ph-negative chronic myeloid leukemia in association with systemic malignant mast cell disease, a patient with acute myeloid leukemia with a t(8;11)(p11;p15), and two cases with T-cell lymphoma, myeloproliferative disorder, and marrow eosinophilia with a t(8;12)(p11;q15) and ins(12;8)(p11;p11p21), respectively. For the patient with the t(8;11), the chromosome 11 breakpoint was determined to be in the vicinity of NUP98. We conclude that 1) all mRNA fusions in EMS result in splicing to FGFR1 exon 9 but breakpoints in FOP are variable, 2) two-color FISH can identify patients with EMS, and 3) the t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11p21) are novel karyotypic changes that most likely involve FGFR1.

The t(8;9)(p22;p24) Is a Recurrent Abnormality in Chronic and Acute Leukemia that Fuses PCM1 to JAK2

“…We identified seven t(8;9) patients for whom the breakpoints assigned by cytogenetics varied from 8p21-23 and 9p23-24, although in some cases the precise band of breakage was reported as uncertain. To our knowledge, this translocation has not been described before as a recurrent abnormality, although one other patient with atypical CML has been described (13) and we have previously reported case 2 as being negative for rearrangement of FGFR1 at 8p11-12 (14). Five patients presented with a CML-like disease (atypical CML, chronic eosinophilic leukemia, or related disorder), one with acute myeloid leukemia secondary to myelofibrosis, and one with pre-B acute lymphoblastic leukemia.…”

Tyrosine kinase fusion genes in chronic myeloproliferative diseases

“…12-19 Disruption 20,21 Although the numbers of patients in the literature are small, there are suggestions that different FGFR1 partner genes are associated with subtly different disease phenotypes. For example, two patients with a t(6;8) and a FOP-FGFR1 fusion were diagnosed initially as having polycythemia vera.…”

FGFR1 (Fibroblast Growth Factor Receptor 1)

“…a polycythaemia vera evolving towards an atypical myeloproliferative disorder, or a T-cell lymphoblastic lymphoma relapsing as an acute myeloblastic leukemia (AML) (Chaffanet et al, 1998;Reiter et al, 1998;Smedley et al, 1998;Xiao et al, 1998;Popovici et al, 1999;Guasch et al, 2000;Mugneret et al, 2000;Demiroglu et al, 2001;Fioretos et al, 2001;Sohal et al, 2001;Roy et al, 2002;Guasch et al, 2003;Grand et al, 2004;Vizmanos et al, 2004;Belloni et al, 2005;Walz et al, 2005;De Melo and Reid, 2006;Etienne et al, 2007;Hidalgo-Curtis et al, 2008;Mozziconacci et al, 2008;Park et al, 2008;Richebourg et al, 2008). The myeloproliferative syndrome transforms rapidly into a myelomonocytic leukemia.…”