Myeloid Leukemia

108 Campbell
ABL fusion on der(22) and an ABL-BCR fusion on the derivative chromosome
9, der(9).
The development of fluorescence in situ hybridization (FISH) and probes to
detect the presence of the ABL and BCR genes enabled the BCR-ABL fusion to
be visualized as co-localization of signals that could be identified in both
metaphase chromosome spreads and also in nondividing interphase cells. Being
able to detect a BCR-ABL fusion in interphase cells also opened up the possibility
of detecting minimal residual disease (MRD) via FISH in patients after
therapy or stem cell transplantation. However, the first BCR/ABL probes available
suffered from a relatively high false-positive rate, with accidental colocalization
of signals observed in approx 5% of interphase cells on normal
control slides (2). A second generation of probes was developed, so that either
an extra signal remained on the der(9) proximal to the breakpoint or a second
fusion signal was generated on the der(9) in the presence of the
t(9;22)(q34;q11·2) (3).
Study of CML cases using second-generation probes identified a subset of
patients with CML who appeared to have a sub-microscopic interstitial deletion
of the der(9) in the region of the ABL-BCR fusion. Approximately 15% of
patients with the standard t(9;22)(q34;q11·2) and a higher percentage of patients
with complex translocations showed evidence of an interstitial deletion
that involved both 9q and 22q sequences on the der(9) (see Fig. 1). In some
cases, these deletions appeared to extend for megabases on either side of the
9q34;22q11·2 breakpoint. It was also determined that the deletion had occurred
at the time of translocation and was either present or absent in all cells containing
the t(9;22) (4–7).
Importantly, a der(9) deletion appeared to influence prognosis. Patients with
der(9) deletions were shown to have an inferior outcome compared with those
who showed no evidence of a deletion. In a study by Sinclair et al. (4), the
median survival of CML patients with a der(9) deletion was 36 mo vs >90 mo
for patients with no deletion. The deletion status was independent of either the
Sokal or the Hasford/European prognostic scoring systems. Deletion status
appeared to predict outcome in patients treated with hydroxyurea or interferon
or, preliminary evidence suggested, stem cell transplantation.
The mechanism by which the deletion confers an inferior outcome has
remained uncertain. Patients with a deletion failed to express the ABL-BCR
transcript, but the effect on prognosis appeared to be independent of ABL-BCR
expression (8,9). The most likely explanation for the effect on outcome appears
to be that the deletion removed an as yet unidentified tumor suppressor
gene or genes. When a third chromosome has been involved in a complex 9;22
translocation, the deletion has been shown to involve the third derivative chromosome
as well. Anelli et al. described a t(9;22;11) with loss of 9q34, 22q11·2,