The Principles of Clinical Cytogenetics - Extra Materials - Springer

392 Rizwan Naeem
As lymphocytes differentiate and mature, the structural changes they undergo are accompanied by
functional changes. The principal change occurring in the maturation of immature lymphoblasts to
lymphocytes is the somatic recombination of the immunoglobulin genes. Cytogenetic abnormalities
play an important role in diagnosis, as well as in defining the treatment and in evaluating prognosis
and risk factors. The cytogenetic abnormalities in precursor B-cell lymphoblastic leukemia/lymphoma
fall into several groups as follows:
• Hypodiploid
• Hyperdiploid with fewer than 50 chromosomes
• Hyperdiploid with more than 50 chromosomes
• Translocations
t(9;22)(q34;q11.2); BCR/ABL1
t(variable;11q23); MLL rearranged
t(12;21)(p13;q22); TEL/AML1
t(1;19)(q23;p13.3); PBX/E2A
• Pseudodiploid
With current treatment protocols, cases that are hyperdiploid with chromosome numbers between
51 and 65 carry a good prognosis. The karyotypes of patients with more than 50 chromosomes have
certain features in common, such as extra copies of chromosome X, 4, 6, 10, 14, 17, 18, 20, and 21,
duplication of 1q, and i(17q). Gain of chromosome 6 and the combination of trisomies 4 and 10 have
been strongly associated with favorable outcomes. About 3% of cases show triploidy; this is more
frequent in adult than in childhood ALL.
A favorable prognosis is also associated with a (12;21) translocation, which results in the fusion of
the TEL gene at 12p13 with the transcription factor encoding gene AML1, at 21q22, resulting in
compromised AML1 transcriptional activity. The chimeric fusion gene is associated with superior
treatment outcomes, with relapse-free survival seen in about 90% of cases. The prognostic strength
of the TEL rearrangement is independent of other factors. Although this is the most common translocation
in childhood ALL, FISH or an reverse-transcription–polymerase chain reaction (RT-PCR)
assay is required to identify the gene fusion or chimeric transcript, as the translocation is not detectable
with standard cytogenetic analysis. Because of the nature of the chromosome bands involved,
this translocation was not reported until molecular evidence identified it.
In childhood cases, over 50% of patients with hyperdiploid karyotypes or t(12;21) have good
prognoses (101–103).
Several cytogenetic findings are associated with poor prognoses using current treatment protocols.
These include t(9;22), t(4;11), and t(1;19), hypodiploidy, and near-haploidy
As described earlier, t(9;22) (see Fig. 1t) results in fusion of the BCR gene at 22q11.2 with ABL1,
a cytoplasmic tyrosine kinase gene at 9q34. In ALL, this translocation is more frequently seen in
adults and is found in approximately 25% of adult patients. In most childhood cases of ALL a variant
t(9;22) fusion protein, p190, is seen. t(4;11) (see Fig. 1l) results in fusion of the MLL gene at 11q23,
which encodes a putative DNA-binding protein, and the transcription activator AF4 at 4q21. (ALL
with 11q23 abnormalities can also occur as therapy-related leukemia.) t(1;19), found in 25% of childhood
B-ALL with cytoplasmic µ expression, fuses the transcription factor produced by E2A at
19p13.3 with PBX1 at 1q23.
Most hypodiploid cases have a model number of 45 chromosomes and arise from loss of whole
chromosomes, unbalanced translocations, or the formation of dicentric chromosomes. Hypodiploidy
with 30–39 chromosomes is seen in about 2% of adult ALL.
The main clone in near-haploid cases contains at least one copy of each chromosome, with two sex
chromosomes and two copies of chromosome 21 in most cases. In many near-haploid cases, there is
a second abnormal cell line with a hyperdiploid karyotype. This hyperdiploid line usually contains
exactly two copies of all chromosomes in the near-haploid cell line.