Acute Leukemias - Republican Scientific Medical Library

a 8.5 · Cytogenetic and Molecular Abnormalities 125
of the Philadelphia chromosome is associated with uniformly
poor outcomes [21, 26, 34].
Philadelphia chromosome results from a reciprocal
translocation between the long arms of chromosomes
9 and 22 [t(9;22)(q34;q11)], which moves the ABL gene
from 9q34 into the BCR (breakpoint cluster region) region
of chromosome 22q11. The resulting BCR-ABL fusion
gene encodes a tyrosine phosphokinase that is constitutively
active and leads to downstream activation of
several proteins, including the Crkl and AKT pathway,
Ras/Raf-1 pathway, Stat 1 and 5 pathways, plateletderived
growth factor (PDGF), and the c-kit receptor
tyrosine kinase [26, 34, 65]. Depending on the exact
position of the translocated ABL gene (exon b2) within
BCR, three different fusion products can be generated:
p190 (molecular weight 190 kd, exon e1), p210 (exon
b2 or b3), and p230 (exon e19). Patients with CML express
mostly the p210 protein and rarely p230, whereas
ALL patients mainly express p190. Some ALL patients
present with p210 expression, but most of these cases
represent lymphoid blast crises of CML.
8.5.4 12p12.3 Abnormalities
Translocation t(12;21)(p12;q22), which results in the
ETV6 (TEL)-AML1 (CBFA2) fusion protein, is detected
in 20–25% of children with B-cell precursor ALL. This
is the most common cytogenetic–molecular abnormality
in childhood ALL, but is relatively uncommon in
adult ALL (< 5%). Rare cases of prenatal t(12;21) have
been documented, suggesting that the translocation
may not be sufficient for overt leukemia and requires
additional mutations (second hits) that occur after
birth. Because the t(12;21)(p12;q22) translocation is not
detected with conventional cytogenetic studies, FISH
or RT-PCR should be used to identify this abnormality.
Deletion in this region without translocation has also
been reported. The ETV6-AML1 fusion protein in children
with ALL is associated with an excellent prognosis,
with longer event-free and overall survival [18, 20, 43,
65, 73].
8.5.5 11q23 Abnormalities
The MLL (mixed lineage leukemia) gene, located at the
11q23 locus, is involved in translocations onto other
chromosomes as well as duplication. The most common
MLL translocations in ALL are t(4;11)(q21;q23), t(9;11)
(p21;q23), t(11;19)(q23;q13.3), and t(3;11)(q22;q23), which
are associated with poor outcomes and a high incidence
of myeloid marker expression [40, 69].
The ATM (ataxia telangiectasia mutated) gene, also
located near chromosome 11q22-23, is frequently deleted
in ALL. About 16% of pediatric ALL patients have loss
of heterozygosity (LOH) at this locus. Haidar and colleagues
reported that 10 of 36 (28%) adults with ALL
had LOH of the ATM gene [35]. Only one (3%) of the
36 patients showed abnormalities involving chromosome
11q23 by conventional cytogenetic studies, indicating
that most of these deletions are submicroscopic [35,
59]. The presence of this abnormality in adults is associated
with better response to therapy [35].
8.5.6 8q24 Abnormalities
The c-myc gene is located on chromosome 8q24 and can
be translocated into one of the three immunoglobulin
chain loci in Burkitt leukemia: IgH on chromosome
14, Iglambda on chromosome 22, or Igkappa on
chromosome 2. These translocations are detected in
cytogenetic and FISH studies as t(8;14)(q24;q32),
t(8;22)(q24;q11), and t(2;8)(p12;q24). Translocation of
the c-myc gene into the T-cell receptor alpha/delta gene
has been reported in T-cell ALL as translocation
t(8;14)(q24;q11). All these translocations lead to quantitative
increases in the expression of c-myc mRNA and
protein, due to juxtaposition of the c-myc gene to the
Ig or T-cell receptor gene enhancer. The c-myc protein
activates the expression of genes necessary for cells to
enter the S-phase and proliferate. This chromosomal abnormality
is detected in approximately 80% of Burkitt
ALL cases; mechanisms other than translocation are believed
to be responsible for increased expression of the
c-myc gene in the remaining cases [12, 33, 39].
8.5.7 19p13.3 Abnormalities
The E2A gene is located on chromosome 19p13.3. Translocation
t(1;19)(q23;p13) forms the E2A-PBX1 fusion
gene, leading to expression of the E2A-PBX1 fusion protein.
This abnormality is seen in precursor B-cell ALL
and is detected in approximately 5% of pediatric and
3% of adult ALL cases. A similar translocation
t(17;19)(q22;p13) involving the E2A gene results in ex