The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Hematologic Neoplasms 367
or specific probe for disease monitoring and helps in identifying patients who could not be diagnosed
by conventional means. Recurring chromosomal translocations are continuing to be identified, and
the importance of this cannot be underestimated as scientists continue using these translocations to
clone genes and find molecular targets for treatment options. In recent years, we have seen numerous
approaches using microarray CGH or BAC CGH, cDNA, and expression array platforms to better
define cancer and understand the biology of disease by looking at genomic and gene expression data.
Yet, even after so much progress in this field, the cause of chromosome translocations that result
in cancer remains one of the essential unanswered questions. For some translocations, in lymphoid
tumors for example, the involvement of a recombinase enzyme seems fairly clear. For myeloid disorders,
however, there is little evidence that recombinase has a role, and thus the focus is on other DNA
sequences that might predispose to breaks, such as ALU and other repeat sequences, translin, and
topoisomerase II (topo II) sites. The challenge for the future is to match our molecular genetic understanding
with a functional understanding of the genes involved in translocations, the other oncogenes
and tumor suppressor genes in normal cells, the genes that regulate them, and their downstream
targets. This will provide a far more complete and robust understanding of the role that these genes
play in growth and differentiation in normal and malignant cells (6).
In the past, malignant leukemias and lymphomas were classified using various approaches: according
to the clinical course, acute versus chronic, according to the primary site, and according to the
phenotype by FAB classification. In 2001, WHO published its integrated classification, which is
becoming a standard of classification throughout the world. In the WHO classifications, leukemias
are primarily stratified into lineage specific types and then further characterized into clinically significant
subgroups (7). The major disease categories according to the WHO classification are listed
in Table 1. This chapter does not cover every disorder classified by WHO, but, rather, focuses on
those for which at least some cytogenetic data is available.
CHRONIC MYELOPROLIFERATIVE DISEASES (MPDS)
There are many common and consistent, nonspecific chromosomal aberrations in this group of
disorders. Correlation with morphology, flow cytometry, and other laboratory and clinical data is
imperative to make the correct diagnosis. This group of patients needs immediate attention and
aggressive treatment, and if untreated, could die within months of presentation. If properly diagnosed
and treated, patients can survive for many years depending on the disease subtype. So far, aside from
CML, no other category in this group of disorders has shown any specific genetic alteration; however,
activation of tyrosine kinase signal transduction pathways is frequently implicated in their pathogenesis
(8–10).
Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) is the paradigm of this category and is an excellent example
of how genetic information and advancement in technology have contributed to the diagnosis, follow-up
after treatment, and, finally, to the development of tailored medicine to treat genomic targets.
This disorder is characterized by abnormal but effective hematopoiesis, resulting in the proliferation
of mature cells, with high peripheral blood levels of one or more cell lines. Patients with CML often
present with hepatosplenomegaly, which probably results from the high rate of sequestration of mature
cells in these organs. The marrow is usually hypercellular, with mature cells and without dysplasia.
The percentage of blasts is either normal or slightly increased (10%). Importantly, fibrosis is not
a primary occurrence and is probably the result of abnormal production and release of cytokines and
growth factors (7,8).
Chronic myelogenous leukemia is defined as a qualitative disorder originating from two or more
cell types with a multilineage phenotype. CML alone accounts for about 15–20% of all cases of
leukemia. The disease can occur at any age, but the most common age of presentation is between the