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Blood, 1 June 2001, Vol. 97, No. 11, pp. 3581-3588
NEOPLASIA
Primary chromosomal rearrangements of leukemia are frequently
accompanied by extensive submicroscopic deletions and may lead to
altered prognosis
Elena Kolomietz,
Jaudah Al-Maghrabi,
Shawn Brennan,
Jana Karaskova,
Solomon Minkin,
Jeffrey Lipton, and
Jeremy A. Squire
From the Ontario Cancer Institute, Princess Margaret
Hospital, Toronto General Hospital, University Health Network,
Department of Laboratory Medicine and Pathobiology, Medical Biophysics,
and Medicine, Faculty of Medicine, University of Toronto, Toronto, ON,
Canada.
BCR/ABL fluorescent in situ hybridization study
of chronic myeloid leukemia (CML) and Philadelphia+
(Ph+) acute lymphoid leukemia (ALL) indicated that
approximately 9% of patients exhibited an atypical hybridization
pattern consistent with a submicroscopic deletion of the 5' region of
ABL and the 3' region of the BCR genes on the
9q+ chromosome. The CML patients with deletions had a
shorter survival time and a high relapse rate following bone marrow
transplant. Since deletions are associated with both Ph+
CML and ALL, it seemed probable that other leukemia-associated genomic
rearrangements may also have submicroscopic deletions. This hypothesis
was confirmed by the detection of deletions of the 3' regions of the
CBFB and the MLL genes in AML M4 patients with
inv(16) and in patients with ALL and AML associated with MLL gene translocations, respectively. In contrast,
analysis of the AML M3 group of patients and AML M2 showed that similar
large deletions were not frequently associated with the t(15;17) or t(8;21) translocations. Analysis of sequence data from each of the
breakpoint regions suggested that large submicroscopic deletions occur
in regions with a high overall density of Alu sequence
repeats. These findings are the first to show that the process of
deletion formation is not disease specific in leukemia and also
implicate that the presence of repetitive DNA in the vicinity of
breakpoint regions may facilitate the generation of submicroscopic
deletions. Such deletions could lead to the loss of one or more genes,
and the associated haploinsufficiency may result in the observed
differences in clinical behavior.
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