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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1197-1207
The Nuclear Topography of ABL, BCR, PML, and RAR Genes:
Evidence for Gene Proximity in Specific Phases of the Cell Cycle
and Stages of Hematopoietic Differentiation
Hélia Neves,
Carlos Ramos,
Maria Gomes da Silva,
António Parreira, and
Leonor Parreira
From the Institute of Histology and Embryology, Lisbon Medical
School, Lisbon, Portugal; and the Service of Hematology, Portuguese
Institute of Cancer, Lisbon, Portugal.
The mechanisms whereby chromosomal translocations are consistently
associated with specific tumor types are largely unknown. A generally
accepted hypothesis is that the physical proximity of the involved
chromosomal regions may be one important factor in the genesis of these
phenomena. Accordingly, a likely possibility is that such a proximity
may occur in a cell-lineage and cell-differentiation stage-specific
manner. In this work, we have addressed this issue using as models the
ABL and BCR genes of t(9;22) and the PML and RAR genes of t(15;17).
By using in situ hybridization and confocal microscopy, we have
measured the distances between these two pairs of genes in
three-dimensionally preserved hematopoietic cells belonging to
different cell lineages, at various stages of differentiation, and at
various stages of the cell cycle, with the following results. (1)
Intergenic distances vary periodically during the cell cycle and a
significant association of ABL with BCR and of PML with RAR is seen
at the transition between S and G2, which persists during G2 and
prophase (such a behavior is not observed for distances between ABL or
PML and the  -globin genes, used as a control). (2) The proportion of
cells in which PML and RAR or ABL and BCR are closely associated is
higher in hematopoietic precursors than in B-lymphoid cells (whereas
the distances between ABL or PML and the -globin genes are not
affected by cell type). (3) When intergenic distances in unstimulated
bone marrow CD34+ cells were compared with those in
CD34+ cells treated with interleukin-3 (IL-3), a trend
towards a higher proximity of the ABL and BCR genes in the former and
of the PML and RAR genes in the latter is observed. (4) Analysis of
B-lymphoid cells during mitosis shows that intergenic distances at
metaphase are strongly influenced by physical constraints imposed by
the chromosomal location of the gene, by the size of the respective chromosome, and by the geometry of the metaphase plate. These findings
suggest that intrinsic spatial dynamics, established early in
hematopoiesis and perpetuated differentially in distinct cell lineages,
may facilitate the collision of individual genes and thus reciprocal
recombination between them at subsequent stages of hematopoietic differentiation.
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