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Distinct ongoing Ig heavy chain rearrangement processes in childhood B-
precursor acute lymphoblastic leukemia
EJ Steenbergen, OJ Verhagen, EF van Leeuwen, AE von dem Borne and CE van der Schoot
Central Laboratory of The Netherlands Red Cross Blood Transfusion Service,
Amsterdam.
Acute lymphoblastic leukemia (ALL) is thought to arise from the clonal
expansion of a single transformed precursor cell. However, an oligoclonal
Ig heavy chain (IgH) rearrangement pattern has been observed in 30% of ALL
patients and was shown to be the result of ongoing rearrangement events.
The extent and nature of these ongoing rearrangement processes in
individual patients has so far remained obscure. We performed a detailed
analysis of leukemic VHDJH rearrangements in three children with
B-precursor ALL at diagnosis and one B-lymphoid blast crisis of a child
with Ph+ chronic myeloid leukemia at diagnosis and relapse. The children
were selected because they presented with multiple IgH rearrangements on
Southern blot analysis. Polymerase chain reaction analysis of leukemic
cells from two B-precursor ALL patients showed exclusively two groups of
related sequences resulting from VH gene replacement events. Most VH gene
replacements involved 3' located acceptor VH genes. Analysis of cells from
the other B-precursor ALL patient showed exclusively related sequences as a
result of VH gene joinings to a pre-existing DJH rearrangement. In the
B-lymphoid blast crisis, a single germline precursor cell had generated
multiple unrelated rearrangements and additional groups of related
rearrangements resulting from VH to DJH joinings. Direct proof for the VH
to DJH joining mechanism was obtained by amplification of the expected
preexisting DJH rearrangements. Our findings suggest that the pattern of
ongoing rearrangements in an individual patient reflects the IgH
rearrangement status of the precursor cell at the time of malignant
transformation. Sequence analysis of VHDJH rearrangements at diagnosis may
therefore allow a prediction of the reliability of complementarity
determining region 3 probes for the detection of minimal residual disease.
Volume 82,
Issue 2,
pp. 581-589,
07/15/1993
Copyright © 1993 by The American Society of Hematology
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