tyrosine kinase fusion proteins
The Philadelphia chromosome and the reciprocal translocation t(9;22)(q34.1;q11.23)
The classic example of a cytogenetic abnormality leading to the formation of a chimeric fusion gene is the Philadelphia chromosome, a truncated chromosome 22 that is present in virtually all patients with chronic myeloid leukemia, in approximately 20% of patients with acute lymphoblastic leukemia, and in rare cases of acute myeloid leukemia.
The Philadelphia chromosome is the result of a reciprocal translocation, t(9;22)(q34.1;q11.23), in which sequences of the BCR gene on band 22q11.23 are joined to portions of the gene encoding the cytoplasmic ABL1 tyrosine kinase on band 9q34.1.
The resulting chimeric protein, BCR-ABL1, contains the catalytic domain of ABL1 fused to a domain of BCR that mediates constitutive oligomerization of the fusion protein in the absence of physiologic activating signals, thereby promoting aberrant tyrosine kinase activity.
The discovery of the Philadelphia chromosome provided evidence that human cancer can arise from acquired genetic alterations in somatic cells.
The aberrant tyrosine kinase signaling in chronic myeloid leukemia led to the use of a selective tyrosine kinase inhibitor, imatinib mesylate, to treat the disease.
Imatinib-resistant kinase domain mutations have been identified as a major cause of relapse during imatinib therapy,20 and this finding, in turn, has led to the development of second-generation BCR-ABL1 inhibitors, such as dasatinib and nilotinib.
Others
Several translocations form tyrosine kinase fusion proteins with constitutive enzymatic activity and some of these fusions also confer sensitivity to tyrosine kinase inhibitors.
These observations highlight the usefulness of conventional chromosomal analysis for guiding the development of new anticancer agents, but the advent of molecular cytogenetic techniques, such as fluorescence in situ hybridization, has further improved the detection of genomic rearrangements that could serve as the basis for new treatments.
Molecular cytogenetic analyses have revealed, for example, that approximately 5% of adults with T-cell acute lymphoblastic leukemia harbor an imatinib-sensitive fusion of ABL1 to the NUP214 gene on band 9q34.1. This fusion occurs on episomes — extrachromosomal elements that are invisible by standard cytogenetic analysis.
Nevertheless, the rarity of cytogenetically visible rearrangements has led to the commonly held belief that tyrosine kinase fusion proteins have no major role in the pathogenesis of carcinomas. This view has recently been challenged by the discovery of a cryptic inversion — inv(2)(p22-p21p23) — in 6.7% of Japanese patients with non–small-cell lung cancer, which results in the formation of a fusion gene comprising portions of EML4 and the gene encoding the ALK receptor tyrosine kinase.
Types
| chromosomal anomalies | fusion genes | Tumors | targeted therapy |
| translocations | - | - | - |
| t(2;5)(p23;p25) | ALK-NPM1 | anaplastic large-cell lymphoma (ALCL) | - |
| t(4;14)(p16;q32) | WHSC1-IGHG1 | multiple myeloma | - |
| t(5;12)(q31-q32;p13) | PDGFRB-ETV6 | myeloid neoplasm associated with eosinophilia | imatinib |
| t(9;22)(q34;q11) | BCR-ABL1 | chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia | imatinib, dasatinib, nilotinib |
| t(12;15)(p13;q25 | ETV6-NTRK3 | congenital fibrosarcoma, cellular mesoblastic nephroma | |
| deletions | - | - | - |
| del(4)(q12q12) | FIP1L1-PDGFRA | myeloid neoplasm associated with eosinophilia | imatinib |
| inversions | - | - | - |
| inv(2)p22-p21p23) | EML4-ALK | non-small cell lung cancer | - |
| episome | - | - | - |
| episome(9q34.1) | NUP214-ABL1 | acute lymphoblastic leukemia |
See also
fusion genes
References
Fröhling S, Döhner H. Chromosomal abnormalities in cancer. N Engl J Med. 2008 Aug 14;359(7):722-34. PMID: #18703475#