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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 225-232
Isochromosome 17q in Blast Crisis of Chronic Myeloid Leukemia and in
Other Hematologic Malignancies Is the Result of Clustered Breakpoints
in 17p11 and Is Not Associated With Coding TP53 Mutations
Thoas Fioretos,
Bodil Strömbeck,
Therese Sandberg,
Bertil Johansson,
Rolf Billström,
Åke Borg,
Per-Gunnar Nilsson,
Herman Van Den Berghe,
Anne Hagemeijer,
Felix Mitelman, and
Mattias Höglund
From the Departments of Clinical Genetics, Oncology, and Medicine,
the Division of Hematology, Lund University Hospital, Sweden; and the
Department of Human Genetics, University of Leuven, Belgium.
An isochromosome of the long arm of chromosome 17, i(17q), is the
most frequent genetic abnormality observed during the disease progression of Philadelphia chromosome-positive chronic myeloid leukemia (CML), and has been described as the sole anomaly in various
other hematologic malignancies. The i(17q) hence plays a presumably
important pathogenetic role both in leukemia development and
progression. This notwithstanding, the molecular consequences of this
abnormality have not been investigated in detail. We have analyzed 21 hematologic malignancies (8 CML in blast crisis, 8 myelodysplastic
syndromes [MDS], 2 acute myeloid leukemias, 2 chronic lymphocytic
leukemias, and 1 acute lymphoblastic leukemia) with i(17q) by
fluorescence in situ hybridization (FISH). Using a yeast artificial
chromosome (YAC) contig, derived from the short arm of chromosome 17, all cases were shown to have a breakpoint in 17p. In 12 cases, the
breaks occurred within the Smith-Magenis Syndrome (SMS) common deletion
region in 17p11, a gene-rich region which is genetically unstable. In
10 of these 12 cases, we were able to further map the breakpoints to
specific markers localized within a single YAC clone. Six other cases
showed breakpoints located proximally to the SMS common deletion
region, but still within 17p11, and yet another case had a breakpoint
distal to this region. Furthermore, using chromosome 17 centromere-specific probes, it could be shown that the majority of the
i(17q) chromosomes (11 of 15 investigated cases) were dicentric, ie,
they contained two centromeres, strongly suggesting that i(17q) is
formed through an intrachromosomal recombination event, and also
implicating that the i(17q), in a formal sense, should be designated
idic(17)(p11). Because i(17q) formation results in loss of 17p
material, potentially uncovering the effect of a tumor suppressor on
the remaining 17p, the occurrence of TP53 mutations was studied
in 17 cases by sequencing the entire coding region. In 16 cases, no
TP53 mutations were found, whereas one MDS displayed a
homozygous deletion of TP53. Thus, our data suggest that there
is no association between i(17q) and coding TP53 mutations, and
that another tumor suppressor gene(s), located in proximity of the SMS
common deletion region, or in a more distal location, is of
pathogenetic importance in i(17q)-associated leukemia.
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