Acute Leukemias - Republican Scientific Medical Library

100 Chapter 6 · Molecular Biology and Genetics
hemi- or homozygous deletions of tumor-suppressor
genes CDKN2A and CDKN2B, and mutually exclusive
overexpression of either the TLX1 or TLX3 (also called
HOX11L2) gene, thus supporting the notion of a multistep
pathogenesis of T-cell ALL [90].
6.4 Numerical Aberrations
6.4.1 High Hyperdiploidy
A high hyperdiploid karyotype, defined by the presence
of > 50 chromosomes, is detected in 2–9% of adult ALL
patients [1, 2, 4–8]. The most common extra chromosomes
in 30 patients with high hyperdiploidy (range
51 to 65 chromosomes) were (in decreasing order) 21,
4, 6, 14, 8, 10, and 17 [4]. In pediatric ALL, gain of X
chromosome appears to be the most common chromosome
abnormality being detected in nearly all children
with a high hyperdiploid karyotype and up to one third
of the patients with low hyperdiploid karyotype (i.e.,
47–50) chromosomes [91]. Interestingly, chromosomes
6, 8, and 10 were also the most common chromosomes
lost in the hypodiploid group, along with chromosome
21. The reason for the involvement of these specific
chromosomes in both types of aberrations is unclear.
Translocation (9;22) is common as a structural aberration
in patients with high hyperdiploidy; it was present
in 11 of 30 (37%) patients in one series [4] and seven of
11 (64%) in another [25]. Patients with hyperdiploidy
and t(9;22) were older and had shorter DFS than those
without t(9;22) [4].
The mechanism leading to hyperdiploidy is unknown.
Several possibilities were suggested including
polyploidization with subsequent losses of chromosomes,
successive gains of individual chromosomes in
consecutive cell divisions, and a simultaneous occurrence
of trisomies in a single abnormal mitosis [92].
Paulsson et al. [93] studied samples from 10 pediatric
ALL patients with hyperdiploidy and demonstrated an
equal allele dosage for tetrasomy 21 suggesting that hyperdiploidy
originated in a single aberrant mitosis.
They further showed that trisomy 8 was of paternal origin
in four of four patients and trisomy 14 was of maternal
origin in seven of eight patients [93]. However, imprinting
was not pathogenetically important in all other
chromosomes. Similar studies are needed in adult ALL
with hyperdiploidy.
The clinical outcome of adult patients with hyperdiploid
karyotypes varies in different series. In two studies,
the outcome of patients with hyperdiploid karyotypes
was better than that of other adult ALL patients
[1, 5, 7] while the other studies [2, 4, 8, 25] showed poor
outcome for these patients except for those with near
tetraploidy [4]. The reason for this discrepancy is unclear.
In two studies [5, 8], the analysis was restricted
to patients with hyperdiploidy without structural abnormalities.
The other studies [1, 2, 4, 7, 25] did not provide
information regarding structural abnormalities. It
may be that T-cell lineage, known to be characterized
by longer DFS and overall survival [94], confers a more
important effect on treatment outcome than does chromosome
number. A study of a larger cohort of adult ALL
patients analyzing the effect of hyperdiploid karyotype
without structural abnormalities as an independent
prognostic factor is warranted.
At the molecular level, high hyperdiploidy in pediatric
patients has a unique gene expression profile [28],
with almost 70% of the genes that defined this group localized
to either chromosome X or 21. The class-defining
genes on chromosome X were overexpressed irrespective
of whether the leukemic blasts had an extra
copy of this chromosome [28]. It is unclear what mechanism
leads to this pattern.
6.4.2 Hypodiploidy
Hypodiploidy is defined by the presence of < 46 chromosomes.
This karyotype is found in 4–9% of adult
ALL patients [1, 4, 5, 7, 95]. These patients tend to be
somewhat younger than patients with a normal karyotype
[4, 5]. Most of these patients have a B-cell lineage
immunophenotype [4, 5, 95], and B-lineage is characterized
by shorter DFS and overall survival than T-lineage
disease [94]. A recent analysis subgrouped patients with
hypodiploidy into those with near-haploidy (23–29
chromosomes), low hypodiploidy (33–39 chromosomes),
and high hypodiploidy (42–45 chromosomes)
[95]. There were only six adult patients in that series,
five of them in the low hypodiploidy group and one
in the high hypodiploidy group. The most common
losses in seven patients with hypodiploidy ranging from
30 to 39 chromosomes involved chromosomes 1, 5, 6, 8,
10, 11, 15, 18, 19, 21, 22, and the sex chromosomes [4].
Only one study reported specifically on hypodiploidy
without structural abnormalities [5]. The impact of