Molecular anatomy of a 5q interstitial deletion
L Nagarajan, B Lange, L Cannizzaro, J Finan, PC Nowell and K Huebner
Department of Hematology, M. D. Anderson Hospital, Houston, TX.
A truncated granulocyte-macrophage colony-stimulating factor (GM-CSF)
allele on a putative 5q- chromosome of HL-60 cells was cloned and, by
comparison with counterpart normal sequences, analyzed for clues to
molecular mechanisms facilitating rearrangement and deletion. Within the
17-kilobase (kb) pair locus surrounding the truncated GM-CSF gene remnant,
there are no fewer than four rearranged genomic fragments that seemingly
derive from chromosome 5 region q21----23. Two of the fragments, which
flank the truncated GM-CSF locus on the 5q-, are contiguous on the normal
chromosome 5, centrometric to the normal GM- CSF allele, indicating at
least one intrachromosomal insertion event, either preceded or followed by
further deletion. Insertion and/or deletion was accompanied by
juxtaposition of LINE sequences to the 5' side of the truncated GM-CSF
locus within the inserted fragment. The entire rearranged locus is embedded
in repetitive sequences, which may have mediated successive insertions or
deletions. The extent of such stepwise deletions, resulting in loss of
genes such as interleukin-3 (IL-3), IL-4, IL-5, and GM-CSF, whose gene
products are critical to differentiation within the lineage of the affected
hematopoietic stem cell, may be mirrored in the heterogeneity of symptoms
and 5q- deletion sizes observed in myelodysplasias and acute leukemias
carrying a 5q- chromosome. Perhaps most significantly, the sequences
surrounding the insertion/deletion region are suggestive of recombination
signals, including direct repeats and mirrored repeats. The site of
insertion of the GM-CSF 3' region into an upstream (centromeric) locus is
flanked by direct repeats; the upstream site into which it is inserted is
also flanked by 12 base pair (bp) direct repeats. After insertion, one
member of each pair of repeats is lost. The organization of this rearranged
locus implies that direct repeats had a role in the intrachromosomal
recombination/deletion event.
Volume 75,
Issue 1,
pp. 82-87,
01/01/1990
Copyright © 1990 by The American Society of Hematology
