Seminars from the University of Minnesota. Chromosome Translocations: Dangerous Liaisons

Many chromosome abnormalities, especially translocations or inversions, are closely associated with a particular morphologic or phenotypic subtype of leukemia, lymphoma, or sarcoma. Cloning the genes at the breakpoints of these rearrangements has provided critical tools for more-precise diagnosis; in some cases the particular diagnosis has prognostic implications. In addition, many of the genes had not been previously identified; their discovery has had a major impact on our understanding of the molecular biology of cancer. One such gene is MLL (myeloid-lymphoid or mixed-lineage leukemia), which is located at chromosome band 11q23. This gene is involved in the 4;11 and 11;19 (p13.3) translocations in acute lymphoblastic leukemia and in the 6;11, 9;11, and 11;19 (p13.1) translocations in acute myeloblastic leukemia. It is also involved in most translocations in infants (under 1 year of age) with acute leukemia and in patients with acute leukemia who were previously treated with drugs that inhibit toposiomerase II. The target gene of MLL is unknown at present, but because of its homology to the trithorax gene in Drosophila, and based on experimental data from mice, it appears to be involved in maintaining the function of some of the homeobox genes. The development of cytogenetic and molecular probes for MLL rearrangements has confirmed that translocations involving MLL are associated with a very poor prognosis. Thus physicians can identify patients with MLL involvement and can institute treatment for these high-risk patients. An increasing understanding of MLL should lead to more-effective targeted therapy.