Acute Leukemias - Republican Scientific Medical Library

126 Chapter 8 · Diagnosis of Acute Lymphoblastic Leukemia
pression of the fusion protein E2A-HLF. The E2A-PBX1
and E2A-HLF fusion proteins are strong transcription
factors that appear to activate several downstream genes
[23, 32, 51, 76]; both are associated with poor outcomes.
8.5.8 5q35 Abnormalities
A recently described cryptic translocation in T-cell ALL,
t(5;14)(q35;q32), moves the HOX11L2 (HOX11like2)(RNX;
TLX3) homeobox gene into close proximity of the CTIP2
gene on chromosome 14. This translocation, which can
be detected with FISH or RT-PCR, leads to overexpression
of HOX11L2. Translocation t(5;14) appears to be restricted
to T-lineage ALL and is more common in children
than adults (22% vs. 13%) [6, 19].
8.5.9 1p32 Abnormalities
The TAL-1 (SCL; TCL-5) gene, located on chromosome
1p32, codes for a 42-kd nuclear protein with a helixloop-helix
DNA binding motif. Found in approximately
25% of cases [3, 41, 63], TAL-1 alterations are the most
common genetic abnormalities in T-cell ALL and
can be formed by translocation or deletion. The
t(1;14)(p32;q11) translocation associates TAL-1 with the
T-cell receptor alpha/delta locus, whereas nonrandom,
submicroscopic interstitial deletions between SIL and
the 5' untranslated region of the TAL-1 gene give rise
to a SIL-TAL-1 fusion transcript. Both alterations disrupt
the coding potential of TAL-1 in a similar manner,
leading to its ectopic expression in T cells.
8.5.10 10q24 Abnormalities
Translocations involving the HOX11 homeobox gene, located
on chromosome 10q24, are present in about 5% of
T-cell ALL cases. Translocation t(10;14)(q24;q11) places
HOX11 under transcriptional control of the T-cell receptor
alpha/delta gene, while translocation t(7;10)(q35;q24)
places it under control of the T-cell receptor beta gene.
Both translocations lead to transcriptional activation of
HOX11 (TLX1; TCL3) [30, 46, 70]. HOX11 overexpression
appears to be a favorable prognostic factor in adult Tcell
ALL [30].
8.5.11 6q Abnormalities
Chromosomal bands 6q15 to 6q23 are frequently deleted
in T- and B-cell ALL. Such deletions have been reported
in approximately 5% of cases, but are believed to be
more frequently detected if PCR analysis of LOH is
used. Translocations involving this region of chromosome
6, including t(6;12)(q23;p13) (ETV-6 gene) and
t(6;11)(q27;q23) (a region close to the MLL gene), have
also been reported. There is a suggestion that this abnormality
is associated with more aggressive disease
[17, 38, 54, 74].
8.5.12 9q32 Abnormalities
The TAL-2 gene encodes a helix-loop-helix protein, a
transcriptional factor that activates various genes and
leads to cellular proliferation [84]. The TAL-2 gene is activated
by translocation t(7;9)(q34;q32), which juxtaposes
it with regulatory elements of the T-cell receptor
beta gene. This abnormality is rare and best detected by
cytogenetic and FISH studies, but its clinical relevance
has not been established.
8.5.13 T-Cell Antigen Receptor Gene
Abnormalities
The genes for T-cell receptors alpha/delta, gamma, and
beta are located on chromosomes 14q11, 7q15, and 7q35,
respectively; the delta receptor gene is located within
the alpha gene. All of these loci are involved in chromosomal
translocations that lead to activation of transcription
factors or oncogenes [65]. The clinical relevance of
the translocations that they are involved with is dependent
on their partner gene. In most of these translocations
the partner genes are deregulated and become under
the influence of the promoter/enhancer of the T-cell
receptors in a fashion similar to that seen in Burkitt leukemia.
8.5.14 13q14 Abnormalities
Deletion of band 13q14 is detected in ALL and many
other leukemias and tumors, suggesting the presence
of tumor suppressor genes in this region. Numerous
genes have been investigated as targets for this deletion,