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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3793-3803
An In Vivo Topoisomerase II Cleavage Site and a DNase I
Hypersensitive Site Colocalize Near Exon 9 in the MLL
Breakpoint Cluster Region
Pamela L. Strissel,
Reiner Strick,
Janet D. Rowley, and
Nancy
J. Zeleznik-Le
From the Department of Medicine, University of Chicago, Chicago, IL.
The human myeloid-lymphoid leukemia gene, MLL (also called
ALL-1, Htrx, or HRX ), maps to chromosomal band
11q23. MLL is involved in translocations that result in de novo
acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),
mixed lineage leukemia, and also in therapy AML (t-AML) and therapy ALL
(t-ALL) resulting from treatment with DNA topoisomerase II (topo II)
targeting drugs. MLL can recombine with more than 30 other
chromosomal bands, of which 16 of the partner genes have been cloned.
Breaks in MLL occur in an 8.3-kb breakpoint cluster region
(BCR) encompassing exons 5 through 11. We recently demonstrated that
75% of de novo patient breakpoints in MLL mapped in the
centromeric half of the BCR between two scaffold-associated
regions (SAR), whereas 75% of the t-AML patient breakpoints mapped to
the telomeric half of the BCR within a strong SAR. We have mapped
additional structural elements in the BCR. An in vivo DNA topo II
cleavage site (induced with several different drugs that target topo
II) mapped near exon 9 in three leukemia cell lines. A strong DNase I
hypersensitive site (HS) also mapped near exon 9 in four leukemia cell
lines, including two in which MLL was rearranged [a t(6;11)
and a t(9;11)], and in two lymphoblastoid cell lines with normal
MLL. Two of the leukemia cell lines also showed an in vivo topo
II cleavage site. Our results suggest that the chromatin structure of
the MLL BCR may influence the location of DNA breaks in both de
novo and therapy-related leukemias. We propose that topo II is enriched
in the MLL telomeric SAR and that it cleaves the DNase I HS
site after treatment with topo II inhibitors. These events may be
involved in recombination associated with t-AML/t-ALL breakpoints
mapping in the MLL SAR.
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