t(8;9)(p12;q33) CNTRL/FGFR1

2004-01-01 Jacques Boyer Affiliation

1.Laboratoire d hématologie, CH du MANS, France

Clinics and Pathology

Disease

Myeloproliferative disorder that is frequently associated with T-cell, or less commonly B-cell non Hodgkin lymphoma.

Phenotype stem cell origin

May involve a stem cell.

Epidemiology

9 cases are described ; sexe ratio : 6M/3F.

Clinics

Agressive disease ; myeloid hyperplasia progressing to myelodysplasia and T or B-cell lymphoma, splenomegaly, lymph node.
High WBC with myelemia with frequently eosinophilia and sometimes monocytosis (near CMLL).

Evolution

The disease transforms to AML or occasionally ALL in a median of 6 months.

Prognosis

Median survival : 12 months.

Cytogenetics

Cytogenetics morphological

This translocation is a variant of the t(8 ;13)(p12 ;q12).

Additional anomalies

+der(9), +21

Genes Involved and Proteins

Gene name

FGFR1 (Fibroblast Growth Factor Receptor 1)

Location

8p11.23

Gene name

CNTRL (centriolin)

Location

9q33.2

Dna rna description

DNA : 26kb - 19 exons
RNA : Three mains transcripts of approximatly 7.5, 4.5 and 1.5 kb. CEP transcripts are barely expressed in thymus and peripheral blood cells.

Protein description

CEP110 gene codes for a 994-amino acid coiled-coil protein with 4 consensus leucine zippers (centrosome associated P110 protein).

Result of the Chromosomal Anomaly

Description

The t(8;9) breakpoint in the FGFR1 gene is localized in exon 8, 12 bp upstream of the exon 8/intron 8 junction. It is distinct from the breakpoints in the t(6;8) and t(8;13) but it preserves the same FGFR1 sequence in the chimeric protein.
The breakpoint in the CEP110 is localized in exon 15.
The translocation leads to the formation of the two reciprocal transcripts.

The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine kinase of 150-kd wich retains most of CEP110 with the leucine zipper motif and the catalytic domain of FGFR1.

The CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm contrasting with the centrosome and membrane localizations of the wildtype respective proteins.

The FGFR1-CEP110 protein contains the FGFR1 N-terminal region with its ligand-binding and transmembrane domains and the CEP110 C-terminal region.

Oncogenesis

Activated aberrant tyrosine kinase are likely to promote leukemogenesis through contitutive activation of the FGFR1 kinase. This activation may be mediated by dimerisation of the portion of the fusion protein wich contains the leucine zippers.
This activation may interacts with the cell proliferation and the apoptose, additional anomalies may also play an important role in the evolution of the disease.

Highly cited references

Pubmed ID	Year	Title	Citations
27245147	2016	FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review).	137
23777766	2013	Dysregulated signaling pathways in the development of CNTRL-FGFR1-induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models.	42
31250523	2019	Targeted therapy and disease monitoring in CNTRL-FGFR1-driven leukaemia.	0

Article Bibliography

Pubmed ID	Last Year	Title	Authors
12094244	2002	Tyrosine kinase fusion genes in chronic myeloproliferative diseases.	Cross NC et al
10688839	2000	FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33).	Guasch G et al
11919391	2002	The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1.	Macdonald D et al
11550283	2001	Identification of four new translocations involving FGFR1 in myeloid disorders.	Sohal J et al

Summary

Fusion gene

CNTRL/FGFR1 CNTRL (9q33.2) FGFR1 (8p11.23) M|CNTRL/FGFR1 CNTRL (9q33.2) FGFR1 (8p11.23) M t(8;9)(p11;q33)|CNTRL/FGFR1 CNTRL (9q33.2) FGFR1 (8p11.23) TIC

Note

8p12 myeloproliferative syndrome (EMS) / stem cell leukemia-lymphoma syndrome (SCLL) belongs to the tyrosine kinase fusion genes chronic myeloproliferative diseases .
It is associated with recurent translocations :

t(8;9)(p12;q33),

t(8;22)(p12;q11)