The Principles of Clinical Cytogenetics - Extra Materials - Springer

372 Rizwan Naeem
Cytogenetics plays an imperative role in the analysis of CML patients. In addition to establishing
diagnosis, it can predict clinical transformation of the chronic phase into accelerated phase or blast
crisis. Some of the common cytogenetic changes that can occur preclinically when patients transform
from chronic phase are trisomy of chromosome 8 and formation of an isochromosome 17q. There are
many genes reported to have mutations in transformed stages, including TP53, RB1, CDKN2A, INK4a,
MINK, AML1, and, EVL1, but their role in transformation, if any, is currently unknown (17,18).
Recently, it has also been shown that in some cases of CML, there is a genomic deletion of chromosomes
9 and 22 sequences around the translocation breakpoints on the derivative chromosomes,
and this might be a cause for poor or worse prognoses in this subgroup of CML patients (19,20).
Sometimes, these deletions are large enough to be detected by fluorescence in situ hybridization
(FISH) analysis (see Chapter 17, Fig. 10). They are more commonly seen in patients with variant
translocations, which account for about 5–10% of all CML cases. There has also been a suggestion
that these deletions occur as a result of mitotic recombination errors when the cells are approaching
accelerated or blast crisis phase. The prognostic value of these additional changes at the time of
diagnosis is significant. In one study, about 9.8% of patients had additional changes at the time of
diagnosis, and this was associated with a shorter median survival of 28 month compared to 48 month
for patients with the Philadelphia rearrangement alone (21).
The molecular consequences of the cytogenetic changes that occur in CML evolution are still not
well understood. Perhaps most of the molecular alterations responsible for disease progression are
not detectable by cytogenetic analysis alone. Common “major route” cytogenetic changes in CML
are trisomy 8, isochromosome 17q (see Fig. 2rr), an additional derivative chromosome 22 (“Philadelphia
chromosome”), and trisomy 19. Less common “minor route” changes include trisomy 21,
loss of the Y chromosome in men, monosomy 7, monosomy or trisomy 17, and a (3;21) translocation
(see Fig. 1k). Patients often present with unique or “patient-specific” secondary changes. These all
have some role to play in transformation to blast crisis and in prognosis. See Table 2.
Recent development of the drug imatinib mesylate (STI571, Gleevec) has considerably
changed the treatment protocol for patients with CML. Gleevec induces remission of CML as fast
as any other therapy and achieves rates of cytogenetic remission far exceeding those induced by
interferon α. It has a toxicity profile as favorable as that of hydroxyurea and far superior to that of
interferon-α (22). The drug rapidly reduces peripheral white cell counts and normalizes marrow
appearance in CML. It also been shown to produce a complete cytogenetic response in a large
number of patients. This treatment approach represents a new class of drugs that attack genomic
targets and serves as a model for new treatment modalities in many other malignancies. Because
this is a recent treatment protocol for CML, there is little correlation with the many different cytogenetic
changes, and there are limited data on the long-term effect of imatinib. A certain percentage
of patients also develop “resistance” to the drug and relapse. Therefore, we will have to wait to
see if this therapy truly fulfills its promise.
A small proportion of patients with chronic myeloproliferative diseases have constitutive activation
of the gene for platelet-derived growth factor-β receptor (PDGFRβ), which encodes a receptor
tyrosine kinase. The PDGFRβ gene is located on chromosome 5q33, and the activation is usually
caused by a translocation, t(5;12)(q33;p13), associated with an ETV6/PDGFRβ fusion. Imatinib
mesylate also inhibits PDGFRβ and KIT kinases and also has impressive clinical efficacy in patients
with rearrangements involving these genes (29,30).
It has been suggested that diagnosis of CML must always be confirmed by proving the presence of
a BCR/ABL1 translocation either by cytogenetics, FISH, or polymerase chain reaction (PCR). Cases
that morphologically suggest CML but are “Philadelphia negative” by routine cytogenetics should be
aggressively pursued by other molecular methods to demonstrate cryptic BCR/ABL1 translocations.
It has also been suggested that molecular confirmation or exclusion of CML in suspected cases is
critical, as that would allow tailored therapy using imatinib. Misdiagnosing CML prevents patients
from getting potential curative therapy, and it has been shown that this therapy is more effective