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Lymphocytic progenitor cell origin and clonal evolution of human B- lineage
acute lymphoblastic leukemia
F Davi, C Gocke, S Smith and J Sklar
Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115,
USA.
At presentation, bone marrow specimens from over 25% of B-lineage acute
lymphoblastic leukemias (ALL) display more than two clonal rearrangements
of immunoglobulin heavy chain (IgH) genes in Southern blot analyses.
Nucleotide sequence analysis has shown predominantly different V(H)DJ(H)
junctions among these genes, leading to the frequent description of such
cases as oligoclonal leukemias. In the present study, we have analyzed the
lgH genes from four patients whose leukemic cells contained different
patterns of lgH gene rearrangements between presentation and relapse.
Nucleotide sequence analysis of the lgH genes showed that three mechanisms
could account for these differences: de novo V(H)DJ(H) rearrangement, V(H)
to DJ(H) recombination, and V(H) replacement. In all cases, more than two
totally different V(H)DJ(H) rearrangements appeared during evolution of the
disease, formally consistent with the conclusion that these tumors were
composed of apparently unrelated clones. However, the retention of some of
the antigen receptor gene rearrangements, as well as the persistence of a
chromosomal marker in two cases, indicated that these leukemias had a
monoclonal origin. These findings support the hypothesis that some ALLs
arise from a lymphoid progenitor cell at a stage of lymphocyte development
before the onset of IgH gene rearrangement. These leukemic lymphocyte
progenitors generate malignant daughter cells capable of an in vivo
maturation that involves the completion of multiple different lgH
rearrangements as well as the modification of preexisting rearrangements by
V(H) to DJ(H) recombination or by a V(H) replacement.
Volume 88,
Issue 2,
pp. 609-621,
07/15/1996
Copyright © 1996 by The American Society of Hematology
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