Some gene rearrangements result in overexpression of proto-oncogenes by removing them from their normal regulatory elements and placing them under control of an inappropriate, highly active promoter or enhancer. Two different kinds of B cell lymphoma provide illustrative examples of this mechanism. In more than 90% of cases of Burkitt lymphoma, the cells have a translocation, usually between chromosomes 8 and 14, that leads to overexpression of the MYC gene on chromosome 8 by juxtaposition with immunoglobulin heavy chain gene regulatory elements on chromosome 14 (
Fig. 6.14 ). In follicular lymphoma, a reciprocal translocation between chromosomes 14 and 18 leads to overexpression of the anti-apoptotic gene, BCL2, on chromosome 18, also driven by immunoglobulin gene regulatory elements.
Other oncogenic gene rearrangements create fusion genes encoding novel chimeric proteins. Most notable
Activation of growth factor signaling pathways oncogene Increased expression of pro-growth genes
Fig. 6.14 ThechromosomaltranslocationsandassociatedoncogenesinchronicmyelogenousleukemiaandBurkittlymphoma.
is the Philadelphia (Ph) chromosome in chronic myeloid leukemia, consisting of a balanced reciprocal translocation between chromosomes 9 and 22 (see
Fig. 6.14 ). As a consequence, the derivative chromosome 22 (the Philadelphia chromosome) appears smaller than normal. This cytogenetic change is seen in more than 90% of cases of chronic myeloid leukemia and results in the fusion of portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9. The few Philadelphia chromosome–negative cases harbor a cryptic (cytogenetically silent) BCR-ABL fusion gene, the presence of which is the sine qua non of chronic myeloid leukemia. As discussed later, the BCR-ABL fusion gene encodes a novel tyrosine kinase with potent transforming activity.
Lymphoid tumors are most commonly associated with recurrent gene rearrangements. This relationship exists because normal lymphocytes express special enzymes that purposefully introduce DNA breaks during the processes of immunoglobulin or T cell receptor gene recombination. Repair of these DNA breaks is error-prone, and the resulting mistakes sometimes result in gene rearrangements that activate proto-oncogenes. Two other types of mesenchymal tumors, myeloid neoplasms (acute myeloid leukemias and myeloproliferative disorders) and sarcomas, also frequently possess gene rearrangements. Unlike lymphoid neoplasms, the cause of the DNA breaks that lead to gene rearrangements in myeloid neoplasms and sarcomas is unknown. In general, the rearrangements that are seen in myeloid neoplasms and sarcomas create fusion genes that encode either hyperactive tyrosine kinases (akin to BCRABL) or novel oncogenic transcription factors. A well-characterized example of the latter is the (11;22)(q24;q12) translocation in Ewing sarcoma. This rearrangement creates a fusion gene encoding a chimeric oncoprotein composed of portions of two different transcription factors called EWS and FLI1.