ALL PATIENTS WITH THE T(11-16)(Q23-P13.3) THAT INVOLVES MLL AND CBP HAVE TREATMENT-RELATED HEMATOLOGIC DISORDERS

The involvement of 11q23-balanced translocations in acute leukemia aft er treatment with drugs that inhibit the function of DNA topoisomerase II (topo II) is being recognized with increasing frequency. We and ot hers have shown that the gene at 11q23 that is involved in all of thes e treatment-related leukemias is MLL (also called ALL1 Htrx, and HRX). In general, the translocations in these leukemias are the same as tho se occurring in de novo leukemia [eg, t(9;11), t(11;19), and t(4;11)], with the treatment-related leukemias accounting for no more than 5% t o 10% of any particular translocation type. We have cloned the t(11;16 )(q23p13.3) and have shown that it involves MLL and CBP (CREB binding protein). The CBP gene was recently identified as a partner gene in th e t(8;16) that occurs in acute myelomonocytic leukemia (AML-M4) de nov o and rarely in treatment-related acute myeloid leukemia. We have stud ied eight t(11;16) patients, all of whom had prior therapy with drugs targetting topo II with fluorescence in situ hybridization (FISH) usin g a probe for MLL and a cosmid contig covering the CBP gene. Both prob es were split in ail eight patients and the two derivative (der) chrom osomes were each labelled with both probes. Use of an approximately 10 0-kb PAC located at the breakpoint of chromosome 16 from one patient r evealed some variability in the breakpoint because it was on the der(l s) in three patients, on the der(11) in another, and split in four oth ers. We assume that the critical fusion gene is 5'MLL/3'CBP. Our serie s of patients is unusual because three of them presented with a myelod ysplastic syndrome (NIBS) most similar to chronic myelomonocytic leuke mia (CMMoL) and one other had dyserythropoiesis; MDS is rarely seen in 11q23 translocations either de novo or with t-AML. Using FISH and the se same probes to analyze the lineage of bone marrow cells from one pa tient with CMMoL, we showed that all the mature monocytes contained th e fusion genes as did some of the granulocytes and erythroblasts; none of the lymphocytes contained the fusion gene. The function of MLL is not well understood, but many domains could target the MLL protein to particular chromatin complexes. CBP is an adapter protein that is invo lved in regulating transcription. It is also involved in histone acety lation, which is thought to contribute to an increased level of gene e xpression. The fusion gene could alter the CBP protein such that it is constitutively active; alternatively, it could modify the chromatin-a ssociation functions of MLL. (C) 1997 by The American Society of Hemat ology.