Acute Leukemias - Republican Scientific Medical Library

a 6.5 · Molecular Aberrations 101
structural abnormalities in patients with hypodiploid
karyotypes in the other series is unknown. Patients with
hypodiploidy have a DFS between 2 to 4 months and
therefore the abnormality is classified as unfavorable.
6.4.3 Trisomy 8
Trisomy 8 in ALL is most often associated with other
karyotypic abnormalities; it is rare as a sole abnormality
[96]. Furthermore, most previous reports have used
karyotype prioritization designs [1–5] to compare the
prognosis of different cytogenetic groups. In these designs,
patients with trisomy 8 were combined with patients
with other cytogenetic aberrations. Only one series
defined patients with trisomy 8 as a separate group
[8]. Twelve of 23 (52%) patients with trisomy 8 also had
t(9;22). However, patients with trisomy 8 without t(9;22)
but with miscellaneous other abnormalities fared as
poorly as those with trisomy 8 and t(9;22) [8]. It is unclear
whether the adverse outcome is due to the other
primary abnormalities or associated with the presence
of trisomy 8. A study of a larger cohort of patients is
warranted in order to analyze the effect of trisomy 8
as an independent prognostic factor in adult ALL patients.
6.4.4 Monosomy 7
As with trisomy 8, monosomy 7 is most often associated
with other karyotypic abnormalities; monosomy 7 as a
sole abnormality is rare in ALL. Only one series defined
patients with monosomy 7 as a separate group [8]. Nine
of 14 (64%) patients with monosomy 7 had t(9;22). Patients
with monosomy 7 without t(9;22) but with miscellaneous
other abnormalities fared as poorly as those
with monosomy 7 and t(9;22) [8]. It is unclear whether
the adverse outcome is due to the other primary abnormalities
or is associated with the presence of monosomy
7. A study of a larger cohort of adult ALL patients is warranted
in order to analyze the independent effect of
monosomy 7 on prognosis.
6.5 Molecular Aberrations
Molecular aberrations are divided into those that
emerge from gene profiling, specific aberrations, and
polymorphism.
6.5.1 Relapse-Classifying Gene Sets
Several groups have identified distinctive gene sets in
diagnostic samples from patients whose disease relapsed
[28, 29, 97–100]. In spite of the different age
groups studied (pediatric [28, 97, 98] vs. adult [29, 99,
100]), assortment of array platforms, and diverse treatment
protocols, all Affymetrix ALL array data and two
sets of cDNA arrays validated the predictability of these
gene sets to delineate the known cytogenetic prognostic
groups [101]. Further, in at least two comparison analyses,
a correlation between the relapse-classifying gene
sets ([97, 100] and [28, 29]) was detected. Utilization of
these gene sets to predict relapse risk and adjust treatment
is awaiting validation in prospective trials. Nevertheless,
some of these genes, such as c-MER, are being
targeted for therapy.
6.5.2 Resistance-Classifying Gene Sets
A different analysis was completed when leukemia cells
were tested for in vitro sensitivity to the four most commonly
used drugs in ALL, i.e., prednisolone, vincristine,
asparaginase, and daunorubicin [102]. Interestingly,
only three genes for which results were significant
in these analyses, RPL6, ARHA, and SLC2A14, have previously
been associated with resistance to doxorubicin.
Gene expression profiles that differed according to sensitivity
or resistance to the four drugs were compared
with treatment outcome. These two gene sets were significantly
and independently predictive of outcome.
They are now being analyzed in prospective studies to
tailor treatment according to patterns of resistance.
6.5.3 Smad3
Smad [Sma and Mad (Mothers against Decapentaplegic)]
3 is involved in signal transduction from the transforming
growth factor (TGF)-b superfamily of receptors
to the nucleus [103]. Smad3 protein was recently shown