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Section III
Figure S2
Figure S2. Characteristics
of AML cases clustered in Figure 2 using
the top 50 class discriminating genes. The
dendogram generated in Figure 2 is reproduced
in this figure, with the sample number,
genetic lesion, karyotype, and FAB morphology
indicated next to each case.
Close examination of the
dendogram shown in figure S2 above suggests
the existence of several distinct subgroups
within the cases with MLL chimeric
fusion genes. Clustered within one of the
major branches of the dendogram are 80% of
the MLL cases along with two non-MLL cases
(Figure 2 and Figure 2S). The cases within
this cluster are characterized by FAB-M5a
morphology (90%) and include all t(9;11) and
t(10;11) cases along with several other rarer MLL translocations.
The two non-MLL cases each have M5a
morphology. The remaining 4 MLL cases
cluster together on a separate branch along
with one non-MLL case. Within this
cluster are both t(11;19) cases along with
a t(6;11) and t(1;11). The single non-MLL case
within this cluster had M5a morphology. Interestingly,
the 4 non-MLL cases that separate the
two major MLL clusters include two
cases with a t(16;21)(p11.2;q22). The molecular
targets of this translocation encode FUS-ERG 4,5 .
Collectively, these data suggest that the
variation in gene expression signatures among
cases with MLL chimeric fusion genes
is likely to result not only from differences
in the nature of the MLL translocation,
but also from differences in the extent of
differentiation and the range of secondary
mutations required for induction of a full
leukemic phenotype. Although two cases lacking MLL chimeric
fusion genes tightly clustered with the MLL cases,
their expression signatures differed enough
from true MLL chimeric fusion gene
cases so that they were appropriately classified
using supervised learning algorithms.
Similar to MLL cases,
two subgroups of CBFb-MYH11 expressing
leukemias were suggested by this analysis,
along with a group of five “other” cases
that lacked evidence of CBFb-MYH11 but
nevertheless clustered with these cases (Figure
2 and Figure 2S). Within this extended cluster
the majority (90%) of the cases had FAB-M4/M4E/M5
morphology, including the five non-CBFb-MYH11 cases.
One group of the CBFb-MYH11 cases (6/14),
expressed a set of genes that were also overexpressed
in the five “other” cases, and
in a subset of cases with MLL chimeric
fusion genes (Figure 2), whereas the other
subgroup of CBFb-MYH11 cases (8/14
cases), expressed these genes at a lower level.
Moreover, the later cases also expressed a
small set of genes that were overexpressed
in AML1-ETO leukemias (Figure 2). A
careful analysis of the morphology and cytogenetics
of the CBFb-MYH11 expressing cases
failed to reveal any significant differences
between these two potential subgroups. Because
of the marked variability in genomic breakpoint
location in both the CBFb and MYH11 genes,
we did not try to correlate these features
with the observed pattern of clustering in
this relatively small cohort of cases. Thus,
the underlying reason for the observed heterogeneity
in CBFb-MYH11 expressing cases remains
unknown.
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