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All Patients With the T(11; 16)(q23; p13.3) That Involves MLL and CBP Have Treatment-Related Hematologic Disorders
Janet D. Rowley,
Shalini Reshmi,
Olatoyosi Sobulo,
Tarannum Musvee,
John Anastasi,
Susana Raimondi,
Nancy R. Schneider,
Julio C. Barredo,
Eduardo S. Cantu,
Brigitte Schlegelberger,
Frederick Behm,
Norman A. Doggett,
Julian Borrow, and
Nancy Zeleznik-Le
From the Department of Medicine, Section of Hematology/Oncology, and the Department of Pathology, University of Chicago Medical Center, Chicago, IL; St Jude Children's Research Hospital, Memphis, TN; the Department of Pathology, University of Texas, Southwestern Medical Center, Dallas, TX; Medical University of South Carolina Medical Center, Charlestown, SC; the Department of Human Genetics, the University of Kiel, Kiel, Germany; the Life Sciences Division and Center for Human Genome Studies, Los Alamos National Laboratory, Los Alamos, NM; and the Cancer Research Center, Massachusetts Institute of Technology, Cambridge, MA.
The involvement of 11q23-balanced translocations in acute leukemia after treatment with drugs that inhibit the function of DNA topoisomerase II (topo II) is being recognized with increasing frequency. We and others have shown that the gene at 11q23 that is involved in all of these treatment-related leukemias is MLL (also called ALL1, Htrx, and HRX). In general, the translocations in these leukemias are the same as those 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% to 10% of any particular translocation type. We have cloned the t(11; 16)(q23; p13.3) and have shown that it involves MLL and CBP (CREB binding protein). The CBP gene was recently identified as a partner gene in the t(8; 16) that occurs in acute myelomonocytic leukemia (AML-M4) de novo and rarely in treatment-related acute myeloid leukemia. We have studied eight t(11; 16) patients, all of whom had prior therapy with drugs targetting topo II with fluorescence in situ hybridization (FISH) using a probe for MLL and a cosmid contig covering the CBP gene. Both probes were split in all eight patients and the two derivative (der) chromosomes were each labeled with both probes. Use of an approximately 100-kb PAC located at the breakpoint of chromosome 16 from one patient revealed some variability in the breakpoint because it was on the der(16) in three patients, on the der(11) in another, and split in four others. We assume that the critical fusion gene is 5'MLL/3'CBP. Our series of patients is unusual because three of them presented with a myelodysplastic syndrome (MDS) most similar to chronic myelomonocytic leukemia (CMMoL) and one other had dyserythropoiesis; MDS is rarely seen in 11q23 translocations either de novo or with t-AML. Using FISH and these same probes to analyze the lineage of bone marrow cells from one patient with CMMoL, we showed that all the mature monocytes contained the 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 involved in regulating transcription. It is also involved in histone acetylation, which is thought to contribute to an increased level of gene expression. The fusion gene could alter the CBP protein such that it is constitutively active; alternatively, it could modify the chromatin-association functions of MLL.
Blood, Vol. 90 No. 2 (July 15), 1997:
pp. 535-541
© 1997 by The American Society of Hematology.
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