Blood, 1 May 2003, Vol. 101, No. 9, pp. 3343-3343
Why do some childhood ALLs relapse?
Leukemogenesis involves sequential acquisition of mutations in
several genes. Various chromosome translocations occur early in
leukemogenesis and may be initiating events, but are not sufficient to
cause leukemia. The most common translocation in childhood ALL is a
cryptic t(12;21) that produces a TEL-AML1 fusion protein. These and
other translocations often occur in utero, with full-fledged leukemia
developing years later following additional mutations in cells from the
translocation-positive preleukemic clone.
Why do some childhood ALLs relapse? Several possibilities, not mutually
exclusive, exist. Prevailing theories include outgrowth of cells that
contain additional mutations and re-emergence of dormant cells from the
original clone. It is also possible that the "original" leukemia
was cured, but a "new" leukemia developed because new cooperating
mutations occurred in the ancestral translocation-positive preleukemic clone.
In this issue, Konrad and colleagues (page 3635) examined this question
by using antigen-receptor gene rearrangements and TEL deletions that occur in concert with
TEL-AML1 fusion to track cells from different stages in
leukemogenesis. They showed previously that some cases of late relapse
are not re-emergence of the fully leukemic clone but are due to
outgrowth of a sibling clone that shares the same ancestral
TEL-AML1 fusion gene but contains different cooperating
TEL deletions. They now confirm and extend their earlier findings. Identical TEL-AML1 genomic fusion sequences in
diagnostic and relapse specimens prove that they were derived from the
same ancestral clone. But the presence of different antigen-receptor rearrangements showed that these were sibling clones that had developed
along divergent pathways. The clone dominant at diagnosis was
undetectable at relapse, suggesting that it had been cured. Remarkably,
the clone dominant at relapse was present at very low
(0.1-0.01%) levels at initial diagnosis. The relapse clones disappeared slowly at diagnosis but responded rapidly to therapy at
relapse, demonstrating different biology at different stages of
disease. Left unanswered is the critical question of whether the rare
relapse clone cells present at initial diagnosis were fully leukemic at
that time or were still in the preleukemic or almost leukemic phase.
These observations provide fascinating insights into leukemia biology
and how childhood ALL is, or is not, cured. Important observations such
as these always raise additional questions. For cure to occur, is it
critical to eliminate every cell in the leukemic clone? What about
cells from the ancestral preleukemic clone; must they be eradicated? It
has never been clear why prolonged low-intensity maintenance
chemotherapy is so important in childhood ALL. It isn't needed for
Burkitt leukemia, a much more aggressive disease. Perhaps
maintenance therapy treats the ancestral preleukemic clone. We know
that chemotherapy treatment can cause leukemia. Many children with ALL
who are cured today could also be cured with less therapy. Could this
overtreatment increase the risk of relapse by exposing preleukemic
cells to potentially mutagenic agents? Secondary mutations provide a
tool to address these questions. We will learn more in the coming
years; some of what we learn may surprise us.
Stephen P. Hunger
University of Florida College of
Medicine
