Fusion Translocation

R9. Remstein, E. D., James, C. D., and Kurtin, P. J., Incidence and subtype specificity of API2-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas. Am. J. Pathol. 156,1183-1188 (2000). 

The presence of chromosomal translocations is a consistent feature of many leukemia s, lymphomas, and certain solid tumors. At the genetic level, these events can either deregulate an intact gene by disruption or removal and replacement of the adjacent controlling elements, or create a new fusion gene that express the N-terminus of one protein fused to the C-terminus of another protein. 

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

A well-known use of molecular methods is in the study of chromosomal translocations. Thus, in Philadelphia chromosome (ph1) positive chronic myelogenous leukemia (CML), the C-abl oncogene on chromosome 9 is translocated to a region on chromosome 22 called the breakpoint cluster region, or bcr. This (t9 22) translocation results in production of an abnormal fusion protein... 

Figure 2. Genetic aberrations observed in HAT genes, (a) Schematic representation of a balanced chromosomal translocation. These translocations result in the formation two new fusion genes, which can give rise to one or two fusion proteins, (b) Examples of nonsense (RTS patient RT163.1), missense (RT209.1), deletion (followed by frame shift RT231.1) mutations, as well as sphee site acceptor (RT211.3) or splice site donor (RT39.1) mutations...

Figure 4. Leukaemic gene fusions involving HATs. (a) The t(8 16) translocation result in the MOZ-CBP fusion protein, while inv(8) gives rise to MOZ-T1F2. (b) Hypothetical model to explain how MOZ-T1F2 and MOZ-CBP fusions result in a similar leukaemia cell phenotype. See text for details, (c) The t(ll 16) and t(l 1 22) result in the MLL-CBP and MLL-p300 gene fusions, respectively...

Crowley JA, Wang Y, Rapoport AP, Ning Y (2005) Detection of MOZ-CBP fusion in acute myeloid leukemia with 8 16 translocation. Leukemia 19 2344-2345 Dash A, Gilliland DG (2001) Molecular genetics of acute myeloid leukaemia. Best Pract Res Clin Haematol 14 49-64... 

Figure 2. Chromosomal translocations leading the production of a MYST HAT fusion protein and cancer, (a) structure of different MYST HAT fusion proteins leading to cancer. Numbers indicate amino acid positions at break points, (b) Model for die consequences of EPCl-PCL fusion on chromatin function...

Kitabayashi 1, Aikawa Y, Nguyen LA, Yokoyama A, Ohki M (2001a) Activation of AMLl-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. Embo J 20 7184-7196 Kitabayashi 1, Aikawa Y, Yokoyama A, Hosoda F, Nagai M, Kakazu N, Abe T, Ohki M (2001b) Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8 22)(pll ql3) chromosome translocation. Leukemia 15 89-94... 

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