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t(6;8)(q27;p12) FGFR1OP/FGFR1

Written2007-05José Luis Vizmanos
Departamento de Genética, Facultad de Ciencias, Universidad de Navarra, 31008 Pamplona, Navarra, Espana
This article is an update of :
2000-12Marie-Josçphe Pébusque
INSERM U119, IFR 57, 27 Blvd Lei Roure, 13009 Marseille, France

(Note : for Links provided by Atlas : click)


ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9967/3 Myeloid and lymphoid neoplasms with FGFR1 rearrangement
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
Atlas_Id 1090
  G-band analysis. Partial karyotype showing the t(6;8)(q27;p12); courtesy José Luis Vizmanos.

Clinics and Pathology

Disease BCR-ABL negative chronic myeloproliferative disease associates with 8p11 chromosomal rearrangements and a clinical entity named "8p11 myeloproliferative syndrome" (EMS) or "stem cell leukemia/lymphoma" (SCLL) syndrome. These chromosomal rearrangements fuse FGFR1 (a receptor tyrosine kinase gene) with other genes resulting in new chimeric genes which are translated in constitutionally activated FGFR1-like proteins. This is a multilineage disorder with combined occurrence of myeloid malignancy and T- cell NHL, or myeloid metaplasia.
Phenotype / cell stem origin The same t(6;8)(q27;p12) is found both in the bone marrow and in the lymph node: the multilineage involvement suggests the malignant transformation of a primitive hematopoietic stem cell.
Epidemiology Rare, very few cases described with this translocation (eight until date, four female and four male). A higher number have been described with other FGFR1 fusions, mainly t(8;13) and ZNF198-FGFR1 fusion.
Clinics This is a myeloproliferative aggressive disease; complex picture of myeloid hyperplasia progressing to myelodysplasia and T- lymphoma, and acute myeloid leukemia; enlarged lymph node infiltrated by myeloid blast cells; blood data: high WBC (median 40 X 109/l); myelemia; monocytosis and eosinophilia. The clinical phenotype at presentation may vary between different partner genes involved in the FGFR1 fusion and, furthermore, between individuals.
Only eight cases with the t(6;8)(q27;p11) have been reported. Four of these patients had features at presentation and/or a clinical course typical of EMS: malignant T-cell lymphoma and CML, AML/myeloproliferative disease, CML-like disease with eosinophilia that progressed rapidly to AML, and primary AML that evolved to EMS following chemotherapy. Two cases presented with polycytemia vera (PV), one of them progressed to AML after a period of 5 years and the other one progressed to an EMS-like myeloproliferative disorder. The remaining case reported showed a B-ALL at presentation. This phenotype has been also described in the transformation phase of some cases with other FGFR1 fusions.
Treatment EMS or SCLL seems to be refractory to conventional chemotherapy and some good results have been reached with allogeneic stem cell transplantation. Imatinib is not effective against constitutional activated FGFR1, but this disease could be responsive to specific FGFR1 inhibitors.
Evolution CR could be obtained, but is promptly followed by relapse progressing rapidly to an AML, rarely ALL.
Prognosis Median survival: 6 months. Although the number of reported cases is low, EMS seems to be disease with bad prognosis that generally progresses to acute leukemia.


Cytogenetics Morphological Available data shows that sometimes the t(6;8)(q27;p12) is not the sole abnormality. BM: 46,XX,t(6;8)(6pter-6q27::8p12-8pter;6qter-6q27::8p12-8qter) BM: 46,XY,t(6;8)(q27;p11) [100%] BM: 46,XY,t(6;8)(q27;p11) [100%] BM: 46,XY,t(6;8)(q27;p11.2) BM: 46,XX,t(6;8)(q27;p11.2),+8,+10,-18,-19,+dic(18;19)(p11.2;p13.3) BM: 46,XX,t(6;8)(q27;p12),+der(6)add(6)(q27) [66% ]; 46,XX,t(6;8)(q27;p12) [34%] BM: 45,XY,t(6;8)(q27;p12),-7 [100%]
Cytogenetics Molecular Mega YAC 959-A -4 (1260kb) from CEPH; FGFR1-specific cosmid 134.8
Variants t(6;8)(q27;p12) is one of the reported rearrangements of 8p11 that fuses FGFR1 with other partner genes.

Genes involved and Proteins

Gene NameFGFR1 (Fibroblast Growth Factor Receptor 1)
Location 8p11.23
Note This gene is involved in several fusions.
Dna / Rna 24 exons spanning about 55.9 Kb on 8p12. Transcription is from centromere to telomere. Based on Entrez data, FGFR1OP has seven different transcripts. Based on EnsEMBL data it has five different transcripts.
Protein According to UniProt-SwissProt FGFR1 (FGFR1_HUMAN) or fibroblast growth factor receptor 1 is a receptor for basic fibroblast growth factor located in the membrane. Binding of FGF1 and heparin promotes autophosphorylation on tyrosine residues and activation of the receptor. FGFR1 contains 3 Ig-like C2-type (immunoglobulin-like) domains and a protein kinase domain. It belongs to the protein tyrosine kinase family, fibroblast growth factor receptor subfamily.
Defects in FGFR1 have been associated with Pfeiffer syndrome (PS) or acrocephalosyndactyly type V (ACS5), hypogonadotropic hypogonadism (IHH), Kallmann syndrome type 2 (KAL2) ; osteoglophonic dysplasia (OGD) ; or osteoglophonic dwarfism, non-syndromic trigonocephaly or metopic craniosynostosis, and the EMS/SCLL due to fusion with other genes and constitutive activation of this receptor.
Gene NameFGFR1OP (FGFR1 oncogene partner)
Location 6q27
Note This gene is involved only in this fusion.
Dna / Rna 13 exons spanning about 43.2 Kb on 6q27. Transcription is from centromere to telomere. Based on Entrez data, FGFR1OP has two different transcripts. Based on EnsEMBL-Vega data it has up to 6 different transcripts.
Protein According to UniProt-SwissProt FGFR1OP (FR1OP_HUMAN) is a centrosomal protein associated with gamma-tubulin and required for anchoring microtubules to the centrosomes. Other centrosomal proteins have been described as fusion partner of tyrosine kinases like FGFR1.
FGFR1OP is a hydrophilic protein that contains several leucine-rich regions with consensus sequences L-X2-L-X3­5-L-X3­5-L (in some of them leucine is substituted by either valine or isoleucine) in its amino and carboxy termini. It has a putative role as a regulator of normal proliferation and differentiation of the erythroid lineage and could belong to a novel family of the leucine-rich proteins. FGFR1OP also contains a Lis-homology (LisH) motif found in more than 100 eukaryotic proteins. These motifs are believed to be involved in microtubule dynamics and organization, cell migration and chromosome segregation; several of them are associated with genetic diseases.
Its expression is ubiquitous but is higher in heart, liver, muscle, kidney, intestine, colon, adrenal gland, prostate, testis, and pancreas.

Result of the chromosomal anomaly

Hybrid gene
  Schematic representation of the fusion FGFR1OP-FGFR1 resulting from the t(6;8)(q27;p12). Top figure courtesy José Luis Vizmanos : From top to bottom: structure of FGFR1, FGFR1OP and the putative chimeric FGFR1OP-FGFR1. TM, transmembrane domain; TK, tyrosine kinase domain. The breakpoints on FGFR1OP are variable as described in refs. 4, 5 and 10; Bottom figure courtesy Marie-Josèphe Pébusque
Description Three different hybrid genes have been described, based on different breakpoints on the FGFR1OP gene. An in-frame fusion between FGFR1OP exon 6 and FGFR1 exon 9 was described; later, two variants in different patients, both in-frame with FGFR1 exon 9, one of them involving FGFR1OP exon 5 and the other involving FGFR1OP exon 7 was described. The presence of two different transcripts (one with a breakpoint in FGFR1OP exon 6 and the other with a breakpoint in exon 7) was reported.
Transcript 5' FGFR1OP-FGFR1 3'
Detection See ref. 4 below.
Fusion Protein
Description The fusion gene is predicted to encode an aberrant tyrosine kinase composed of the putative leucine-rich N-terminal region of FOP, and the FGFR1 intracellular region. Like other fusions involving RTKs, FGFR1OP-FGFR1 lacks the FGFR1 transmembrane domain.
Oncogenesis Through constitutive activation of FGFR1 signal transduction pathways, via putative dimerization of the fusion protein via the FOP leucine-rich repeats FGFR1OP shares features in common with other tyrosine kinase fusion partners, namely widespread expression and the presence of putative oligomerization domains. There is experimental proof that expression of FOP-FGFR1 in primary bone marrow cells induced by retroviral transduction generates a rapid MPD in mice. However, lymphoproliferation and progression to acute phase were not observed in the murine model.

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.
Case Report t(6;8)(q27;p12) in a new case "8p11 myeloproliferative syndrome"


t(6;8), t(8;9) and t(8;13) translocations associated with stem cell myeloproliferative disorders have close or identical breakpoints in chromosome region 8p11-12.
Chaffanet M, Popovici C, Leroux D, Jacrot M, Adélaïde J, Dastugue N, Grégoire MJ, Hagemeijer A, Lafage-Pochitaloff M, Birnbaum D, Pébusque MJ
Oncogene. 1998 ; 16 (7) : 945-949.
PMID 9484786
Detection and significance of bone marrow infiltration at the time of autologous bone marrow transplantation in Hodgkin's disease.
Chopra R, Wotherspoon AC, Blair S, McMillan AK, Mills W, Fielding AK, Linch DC, Goldstone AH
British journal of haematology. 1994 ; 87 (3) : 647-649.
PMID 7993812
Tyrosine kinase fusion genes in chronic myeloproliferative diseases.
Cross NC, Reiter A
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 ; 16 (7) : 1207-1212.
PMID 12094244
FOP-FGFR1 tyrosine kinase, the product of a t(6;8) translocation, induces a fatal myeloproliferative disease in mice.
Guasch G, Delaval B, Arnoulet C, Xie MJ, Xerri L, Sainty D, Birnbaum D, Pébusque MJ
Blood. 2004 ; 103 (1) : 309-312.
PMID 12969958
The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1.
Macdonald D, Reiter A, Cross NC
Acta haematologica. 2002 ; 107 (2) : 101-107.
PMID 11919391
Structure of the N-terminal domain of the FOP (FGFR1OP) protein and implications for its dimerization and centrosomal localization.
Mikolajka A, Yan X, Popowicz GM, Smialowski P, Nigg EA, Holak TA
Journal of molecular biology. 2006 ; 359 (4) : 863-875.
PMID 16690081
The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1.
Popovici C, Zhang B, Grégoire MJ, Jonveaux P, Lafage-Pochitaloff M, Birnbaum D, Pébusque MJ
Blood. 1999 ; 93 (4) : 1381-1389.
PMID 9949182
Sequential transformation of t(8;13)-related disease: a case report.
Roy S, Szer J, Campbell LJ, Juneja S
Acta haematologica. 2002 ; 107 (2) : 95-97.
PMID 11919389
Identification of four new translocations involving FGFR1 in myeloid disorders.
Sohal J, Chase A, Mould S, Corcoran M, Oscier D, Iqbal S, Parker S, Welborn J, Harris RI, Martinelli G, Montefusco V, Sinclair P, Wilkins BS, van den Berg H, Vanstraelen D, Goldman JM, Cross NC
Genes, chromosomes & cancer. 2001 ; 32 (2) : 155-163.
PMID 11550283
Simultaneous occurrence of a T-cell lymphoma and a chronic myelogenous leukemia with an unusual karyotype.
Vannier JP, Bizet M, Bastard C, Bernard A, Ducastelle T, Tron P
Leukemia research. 1984 ; 8 (4) : 647-657.
PMID 6590932
Clinical variability of patients with the t(6;8)(q27;p12) and FGFR1OP-FGFR1 fusion: two further cases.
Vizmanos JL, Hernández R, Vidal MJ, Larráyoz MJ, Odero MD, Marín J, Ardanaz MT, Calasanz MJ, Cross NC
The hematology journal : the official journal of the European Haematology Association / EHA. 2004 ; 5 (6) : 534-537.
PMID 15570299
A biphenotypic transformation of 8p11 myeloproliferative syndrome with CEP1/FGFR1 fusion gene.
Yamamoto K, Kawano H, Nishikawa S, Yakushijin K, Okamura A, Matsui T
European journal of haematology. 2006 ; 77 (4) : 349-354.
PMID 16879608
A complex of two centrosomal proteins, CAP350 and FOP, cooperates with EB1 in microtubule anchoring.
Yan X, Habedanck R, Nigg EA
Molecular biology of the cell. 2006 ; 17 (2) : 634-644.
PMID 16314388


This paper should be referenced as such :
Vizmanos JL
t(6;8)(q27;p12) FGFR1OP/FGFR1;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version :
History of this paper:
Pébusque, MJ. t(6;8)(q27;p12). Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):37-38.

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes FGFR1 CEP43

Translocations implicated (Data extracted from papers in the Atlas)

 t(6;8)(q27;p12) FGFR1OP/FGFR1

External links

FGFR1OP (6q27) FGFR1 (8p11.23)

Mitelman databaset(6;8)(q27;p12)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9967/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9989/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
Mitelman databaseFGFR1OP/FGFR1 [MCList]  FGFR1OP (6q27) FGFR1 (8p11.23)
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
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