Acute Leukemias - Republican Scientific Medical Library

a 6.3 · Structural Aberrations 97
somes, both in ALL and acute myeloid leukemia (AML)
[31]. While the MLL gene can be amplified in a subset of
AML patients, its amplification is very rare in ALL [32].
The distribution of 11q23/MLL translocation partners
differs between ALL and AML, with t(4;11)(q21;q23)
being by far the most frequent 11q23 translocation in
ALL (see below). The breaks in MLL in most translocations
occur in the 8.3 kb BCR, between exons 8 and 12.
Fusion of a COOH-terminal partner is essential for leukemogenesis,
as expression of the NH2-terminus alone
was not sufficient to immortalize cells [33]. Partial tandem
duplication, described in AML [34], has not been
thus far detected in ALL. MLL translocations have been
described in both de novo and therapy-related disease
[35].
MLL-positive ALL also has a unique gene expression
profile [29, 36]. Specifically, some HOX (homeobox)
genes are expressed at higher levels in MLL-positive
ALL than in MLL-negative ALL [37]. Furthermore, gene
expression profiles predictive of relapse were recently
identified in pediatric MLL-positive ALL in one study
[38] but did not reach statistical significance in the
other [28]. Further work in this area is ongoing.
6.3.3 t(4;11)(q21;q23)
The t(4;11)(q21;q23) is the most frequent chromosomal
rearrangement involving the MLL gene in adult ALL,
being detected in 3–7% of ALL patients, and is associated
with an unfavorable outcome [1–5, 7, 8]. It results
in two reciprocal fusion products coding for chimeric
proteins derived from MLL and from a serine/prolinerich
protein encoded by the AF4 (ALL1 fused gene from
chromosome 4) gene [39]. Studies have revealed different
fusion sequences documenting variable MLL and
AF4 exon involvement in t(4;11) [40–42]. To our knowledge,
the different fusion sequences affect neither disease
characteristics nor outcome.
Griesinger et al. [43] have demonstrated the presence
of MLL-AF4 gene fusions in adult ALL patients
without cytogenetically detectable t(4;11). Another study
analyzed the clinical significance of molecularly detected
MLL-AF4 gene without karyotypic evidence of
t(4;11), and established that patients whose blasts were
MLL-AF4-positive in the absence of t(4;11) had outcome
similar to patients whose blasts were MLL-AF4-negative
[44]. This study suggests that additional treatment is
not needed for patients whose blasts are MLL-AF4-pos-
itive but t(4;11)-negative. Furthermore, the finding of
MLL-AF4 transcripts by nested reverse-transcriptase
(RT) polymerase chain reaction (PCR) in four of 16 fetal
bone marrow samples, five of 13 fetal livers, and one of
six normal infant marrows shows that healthy individuals
carry rare nonmalignant cells with the MLL-AF4
gene fusion and indicates that the presence of MLL-
AF4 is not sufficient for leukemogenesis [44]. Therefore,
to be clinically relevant, the presence of MLL-AF4
should not be detected solely by nested RT-PCR but
confirmed using another technique such as cytogenetic,
Southern blot, and/or FISH analyses.
Secondary cytogenetic aberrations in addition to
t(4;11) are found in approximately 40% of patients [4,
45, 46]. The most common additional changes were
i(7)(q10) and +6 in one series [45] and +X, i(7)(q10),
and +8 in another [46]. With treatment carried out according
to modern risk-adapted therapy, no difference
in outcome was observed between patients with and
without clonal chromosome aberrations in addition to
t(4;11) at diagnosis [46], although this series was relatively
small thus warranting further study of a larger
number of patients with t(4;11) ALL.
Other recurrent, albeit rare in ALL, translocations
include t(6;11)(q27;q23), t(9;11)(p22;q23), t(10;11)
(p12;q23), and t(11;19)(q23;p13.3) [47]. The respective
fusion partners of the MLL gene are AF6, AF9, AF10,
and ENL (eleven-nineteen leukemia). Other less common
MLL partners were also described [48].
6.3.4 del(9p) or t(9p)
Deletions or translocations involving the short arm of
chromosome 9 occur in 5–15% of adult ALL patients
[4, 5, 7, 8]. Most of the breakpoints are located at
9p21, although other breaksites have also been reported.
Anomalies of 9p are most often associated with other
clonal aberrations (in up to 90% of patients), that in almost
one third of the cases include t(9;22) [8]. These
data suggest that del(9p) likely represent secondary cytogenetic
abnormalities.
The genes most commonly involved in del(9p) are
CDKN2A (cyclin-dependent kinase inhibitor 2A, also
known as MTS1 and p16 INK4A ) and CDKN2B (also
known as MTS2 and p15 INK4B ), both located at 9p21
[49, 50] adjacent to each other, with CDKN2B centromeric
to CDKN2A [51]. One report describes these aberrations
to occur frequently in T-lineage ALL [52], while