Fusion Proteins and Diseases


Fusion proteins occur as a result of chromosomal translocations in cancerous cells. The proteins targeted are either transcription factors or tyrosine kinases. The fusion proteins are associated with developmental malignancies and thyroid carcinomas.

Keywords: chromosomal translocations; transcription factors; tyrosine kinase; leukemia; sarcoma; thyroid carcinoma; chromatin; cell‐cycle signaling pathways

Figure 1.

Metaphase spread of an acute myeloid leukemic cell, showing a balanced translocation between chromosomes 11 (green) and 10 (pink). All other chromosomes are in blue. In this case the translocation resulted in an in‐frame fusion of the 5′ end of the MLL gene on 11q23 with the 3′ end of the MLLT10 gene on 10p12.

Figure 2.

One of the effects of chromosomal translocations involving transcription factors. Protein A has a DNA‐binding domain and interacts with protein B with its interactive domain. As a result, protein C is upregulated. As the levels of protein C rise, protein D is also upregulated. Protein D docks on protein B and blocks the A–B interaction (shown by a change in the polarization of the molecule), switching the activation of protein C. As a result of a chromosomal translocation, protein A fuses to B, and B loses its docking domain, thus C becomes constitutionally upregulated.

Figure 3.

Two classes of proteins are involved in the genesis of fusion genes: those that encode transcription factors involved in development (dark gray ellipses), which tend to occur in acute leukemias and sarcomas of childhood; and genes encoding tyrosine kinases (gray ellipses), which are usually associated with chronic myeloid leukemia, lymphoma and thyroid carcinomas.

Figure 4.

Effect of the t(12;21) translocation. The ETV6 gene on chromosome 12p13 encodes a protein with an N‐terminal dimerization motif (PNT) which acts as a repressor, a central NCOR recruiting domain and a C‐terminal DNA‐binding ETS domain. The RUNX1 gene on 21q22 encodes a protein with an N‐terminus DNA‐binding runt domain and a C‐terminus transcriptional activation domain. As a result of the translocation (breakpoints are indicated by arrows), the repressor domain of ETV6 is fused to almost the whole RUNX1 molecule. The fusion gene product is able to competitively repress transcription of RUNX1 target genes. WRPY is a tetrapeptide motif.



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Further Reading

Alcalay M, Orleth A, Sebastiani C, et al. (2001) Common themes in the pathogenesis of acute myeloid leukemia. Oncogene 20(40): 5680–5694.

Arvand A and Denny CT (2001) Biology of EWS/ETS fusions in Ewing's family tumors. Oncogene 20(40): 5747–5754.

Barr FG (2001) Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Oncogene 20(40): 5736–5746.

Elliott B and Jasin M (2002) Double‐strand breaks and translocations in cancer. Cellular and Molecular Life Sciences: CMLS 59(2): 373–385.

Hickman JA (2002) Apoptosis and tumourigenesis. Current Opinion in Genetics and Development 12(1): 67–72.

Look AT (1997) Oncogenic transcription factors in the human acute leukemias. Science 278(5340): 1059–1064.

Pandolfi PP (2001) Histone deacetylases and transcriptional therapy with their inhibitors. Cancer Chemotherapy and Pharmacology 48(supplement 1): 17–19.

Pierotti MA (2001) Chromosomal rearrangements in thyroid carcinomas: a recombination or death dilemma. Cancer Letters 166(1): 1–7.

Ravandi F, Talpaz M, Kantarjian H and Estrov Z (2002) Cellular signaling pathways: new targets in leukemia therapy. British Journal of Haematology 116(1): 57–77.

Varga‐Weisz P (2001) ATP‐dependent chromatin remodeling factors: nucleosome shufflers with many missions. Oncogene 20(24): 3076–3085.

Web Links

ETV6 (ets variant gene 6 (TEL oncogene)); Locus ID: 2120. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2120

MLL (myeloid/lymphoid or mixed‐lineage leukemia (trithorax homolog, Drosophila)); Locus ID: 4297. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4297

RUNX1 (runt‐related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)); Locus ID: 861. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=861

ETV6 (ets variant gene 6(TEL oncogene)); MIM number: 600618. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?600618

MLL (myeloid/lymphoid or mixed‐lineage leukemia (trithorax homolog, Drosophila)); MIM number: 159555. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?159555

RUNX1 (runt‐related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)); MIM number: 151385. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?151385

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How to Cite close
Saha, Vaskar, and Jones, Louise Kathleen(Jan 2006) Fusion Proteins and Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005543]