250
U N I T 3
Hematopoietic Function
Because blood cells circulate throughout the body, these
neoplasms are often disseminated from the onset. The
leukemic cells may also infiltrate the liver, spleen, lymph
nodes, and other tissues throughout the body, causing
enlargement of these organs.
Classification
The leukemias commonly are classified according
to their predominant cell type (i.e., lymphocytic or
myelocytic) and whether the condition is acute or
chronic. Biphenotypic leukemias demonstrate char-
acteristics of both lymphoid and myeloid lineages.
The
lymphocytic leukemias
involve immature lym-
phocytes and their progenitors that originate in the
bone marrow but infiltrate the spleen, lymph nodes,
CNS, and other tissues. The
myelogenous leukemias,
which involve the pluripotent myeloid stem cells in
bone marrow, interfere with the maturation of all
blood cells, including the granulocytes, erythrocytes,
and thrombocytes.
A rudimentary classification system divides leuke-
mia into four types: acute lymphocytic leukemia (ALL),
chronic lymphocytic leukemia (CLL), acute myelocytic
leukemia (AML), and chronic myelocytic leukemia
(CML).
4,7
Among children and adolescents, ALL is the
most common type, accounting for 75% of leukemia
cases. In adults 20 years of age and older, the most com-
mon types are CLL (38%) and AML (30%).
16
Etiology and Molecular Biology
The causes of leukemia are largely unknown and likely
differ among the different types of leukemia. The inci-
dence of acute leukemia among persons who have been
exposed to high levels of radiation is unusually high.
Exposure to ionizing radiation, including medical
radiation used in cancer treatment, increases the risk
of leukemia.
16
Leukemia may occur as a second can-
cer after aggressive chemotherapy for other cancers,
such as Hodgkin lymphoma. Some factors are associ-
ated with increased risk of certain types of leukemias.
16
Exposure to certain chemicals such as formaldehyde
and benzene (a compound in cigarette smoke and gaso-
line) also increases the risk of AML. Family history is
one of strongest risk factors for CLL. The existence of a
genetic predisposition to development of acute leukemia
is suggested by the increased leukemia incidence among
a number of congenital disorders, including trisomy 21
(Down syndrome), neurofibromatosis, and Fanconi ane-
mia.
7,16
In individuals with Down syndrome, the inci-
dence of acute leukemia is 10 to 20 times that of the
general population.
The molecular biology of leukemia suggests that
the event or events causing the disorders exert their
effects through disruption or dysregulation of genes
that normally regulate blood cell development, blood
cell homeostasis, or both. Most commonly, these are
structural changes classified as
translocations
, in which
a part of one chromosome becomes located on another
chromosome and vice versa;
inversions
, in which part of
a chromosome turns upside down and now is in reverse
order but still attached to the original chromosome; and
deletions
, in which part of a chromosome has been lost
(see Chapter 6). It is the disruption or dysregulation of
specific genes and gene products occurring at the site of
these chromosome aberrations that contributes to the
development of leukemia.
17
In many instances, these
genes and their products have been shown to be directly
or indirectly involved in the normal development or
maintenance of the hematopoietic system. Thus, it
would appear that leukemia results, at least in part,
from disruption in the activity of genes that normally
regulate blood cell development. Advances in the under-
standing of the molecular biology of leukemia are begin-
ning to provide a more complete understanding of the
molecular complexity of this disorder for the purposes
of diagnosis, classification, treatment, and monitoring
of clinical outcomes.
One of the more studied translocations is the
Philadelphia chromosome, which was the first chromo-
somal abnormality identified in cancer. The Philadelphia
chromosome translocation represents a reciprocal trans-
location between the long arm of chromosome 22 and
the long arm of chromosome 9.
17,18
During the trans-
location, a large portion of 22q is translocated to 9q,
and a smaller piece of 9q is moved to 22q (Fig. 11-6).
The portion of 9q that is translocated contains
ABL,
Chromosome 9
Chromosome 22
BCR
locus
ABL
proto-
oncogene
BCR
locus
ABL
oncogene
BCR–ABL
hybrid gene
ABL
protein
Normal chromosomes
Myelogenous leukemia
FIGURE 11-6.
The Philadelphia (Ph) chromosome is formed
by breaks at the ends of the long arms of chromosomes 9
and 22, allowing the ABL proto-oncogene on chromosome 9
to be translocated to the breakpoint cluster region (BCR) on
chromosome 22.The result is a new fusion gene coding for
the BCR–ABL protein, which is presumably involved in the
pathogenesis of chronic myelogenous leukemia.
