t(6;8)(q27;p12)

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t(6;8)(q27;p12)

Identity

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 non lymphocytic 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

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 Name FGFR1

Location 8p12

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 Name FGFR1OP (formerly known as FOP, 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.

External links

Other database t(6;8)(q27;p12) Mitelman database (CGAP - NCBI)

Other database t(6;8)(q27;p12) CancerChromosomes (NCBI)

Other database Mitelman database (CGAP - NCBI)

Other database CancerChromosomes (NCBI)

Other database FGFR1 TICdb

Other database	t(6;8)(q27;p12)	Mitelman database (CGAP - NCBI)
Other database	t(6;8)(q27;p12)	CancerChromosomes (NCBI)
Other database	Mitelman database (CGAP - NCBI)
Other database	CancerChromosomes (NCBI)
Other database	FGFR1 TICdb

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.

Bibliography

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

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

A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: a review.

Macdonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1995 ; 9 (10) : 1628-1630.

PMID 7564500

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, Adˆ©laˆØde J, Dastugue N, Grˆ©goire MJ, Hagemeijer A, Lafage-Pochitaloff M, Birnbaum D, Pˆ©busque MJ

Oncogene. 1998 ; 16 (7) : 945-949.

PMID 9484786

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, Grˆ©goire MJ, Jonveaux P, Lafage-Pochitaloff M, Birnbaum D, Pˆ©busque MJ

Blood. 1999 ; 93 (4) : 1381-1389.

PMID 9949182

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

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

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

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

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, Pˆ©busque MJ

Blood. 2004 ; 103 (1) : 309-312.

PMID 12969958

Clinical variability of patients with the t(6;8)(q27;p12) and FGFR1OP-FGFR1 fusion: two further cases.

Vizmanos JL, Hernˆ°ndez R, Vidal MJ, Larrˆ°yoz MJ, Odero MD, Marˆ‚n 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

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

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

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

Contributor(s)

Written 12-2000 Marie-Josèphe Pébusque

INSERM U119, IFR 57, 27 Blvd Leï Roure, 13009 Marseille, France

Citation

This paper should be referenced as such :
Pébusque MJ . t(6;8)(q27;p12). Atlas Genet Cytogenet Oncol Haematol. December 2000 .
URL : http://AtlasGeneticsOncology.org/Anomalies/t68ID1090.html

Vizmanos JL . t(6;8)(q27;p12). Atlas Genet Cytogenet Oncol Haematol. .
URL : http://AtlasGeneticsOncology.org/Anomalies/t68ID1090.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon May 12 18:13:21 2008

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For comments and suggestions or contributions, please contact us

j.l.huret@chu-poitiers.fr.

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 non lymphocytic 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.

Gene Name	FGFR1
Location	8p12
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 Name	FGFR1OP (formerly known as FOP, 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.



	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.

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.

Written	12-2000	Marie-Josèphe Pébusque
		INSERM U119, IFR 57, 27 Blvd Leï Roure, 13009 Marseille, France