1993 Robert R. deVilliers Lecture. Chromosome translocations: dangerous liaisons

Rearrangements involving chromosome band 11q23 are very common in acute leukemia, both lymphoblastic and myeloid (monoblastic), and are less common in lymphoma. Although several different genes have been cloned from 11q23 translocation breakpoints, the great majority involve the MLL (myeloid-lymphoid leukemia) gene. The MLL gene has several different names, ALL1, Htrx, HRX; the central part of the gene codes for multiple zinc fingers which show strong homology to the Drosophila trithorax gene. MLL is involved in four common translocations as well as in 25 uncommon or rare translocations, insertions and deletions. The translocation breakpoints occur within an 8.3kb region which can be detected with a 0.7 kb cDNA probe. Twenty-five percent of patients have a deletion 3' of the breakpoint which includes the zinc finger region. Patients who previously received drugs that inhibit topoisomerase II often develop acute leukemia with translocations involving 11q23. These translocations break MLL in the same 8.3kb region. In the four breakpoints cloned to date, the translocation has led to a fusion gene on the derivative 11 chromosome with a chimeric transcript, consisting of 5' MLL and the 3' segment of the other gene. Although transcripts were also cloned from the other derivative chromosome, all the evidence indicates that the critical fusion gene is on the derivative 11 chromosome. The molecular dissection of these rearrangements will provide insights into the biology of MLL and into the interaction of MLL with topoisomerase II inhibitors. In addition, this research has provided DNA probes that will be important for diagnosis and for monitoring patients during the course of their disease.