The Principles of Clinical Cytogenetics - Extra Materials - Springer

380 Rizwan Naeem
The WHO classification incorporates morphological, immunophenotypic, genetic, and clinical
information to categorize AML. The threshold blast percentage is 20%, compared with 30% in the
FAB classification. The WHO classification is as follows:
• Acute myeloid leukemia with recurrent genetic abnormalities
AML with t(8;21)(q22;q22) (AML1 or CBFα/ETO) (Often FAB M2); see Fig. 1r
AML with abnormal eosinophils; inv(16)(p13q22) or t(16;16)(p13;q22) (CBFβ/MYH11) (often
FAB M4EO); see Fig. 2ccc
Acute promyelocytic leukemia ([AML with t(15;17)(q22;q12)(PML/RARA) and variants] (FAB
M3); see Fig. 1bb.
AML with 11q23 (MLL) abnormalities
• Acute myeloid leukemia with multilineage dysplasia
• Acute myeloid leukemia and myelodysplastic syndrome or therapy-related AML
• Acute myeloid leukemia not otherwise characterized
Because of its heterogeneity, classification of AML into its various biologic entities is necessary
in order to understand its pathogenesis and develop specific treatment approaches. Furthermore, the
presence of chimeric transcripts in leukemic blasts has been shown to be among the most important
independent prognostic parameters in AML. In the WHO classification, genetically defined subgroups
of AML are classified and treatment decisions are often based on these disease-specific genetic
defects. The incidence of abnormal karyotypes in AML is reported to be about 55–78% in adults and
77–85% in children. However, substantial portions of patients with AML show no chromosomal
abnormalities. Recent studies show that cytogenetically normal patients often display submicroscopic
gene alternations that can only be detected by a molecular method. For instance, approximately 6%
of the adult AML patients with normal karyotypes have a partial tandem duplication within the MLL
gene. In addition, over 20% of patients with such intragenic MLL abnormalities demonstrate a mutation/deletion
involving FLT3 (CD135), but this only occurs in 10% of AML cases with MLL translocations
and only in 5% of adult AML with normal MLL status (67).
Cytogenetic abnormalities in AML can be classified into primary and secondary abnormalities.
The primary chromosomal abnormalities are frequently found as the sole karyotypic abnormality and
are often specifically associated with a particular AML subtype. On average, about 55% of AML
patients with a karyotypic abnormality have only one recognizable rearrangement. These primary
chromosomal abnormalities are assumed to play an essential role in the early stages of tumorigenesis.
On the other hand, secondary chromosomal abnormalities seem to play an important role in the progression
of the disease, but they are rarely found alone. Many of the primary chromosomal abnormalities
in AML are balanced translocations between two different chromosomes or inversions within
a single chromosome; t(8;21), t(15;17) and inv(16) are examples. These balanced rearrangements
disrupt critical genes involved in normal hematopoiesis, resulting in an abnormal process. On the
other hand, many unbalanced abnormalities, including deletions or gains and losses of entire chromosomes,
are thought to be primary abnormalities, but the pathogenic mechanism has not been resolved
in any of these because of the large number of genes involved. The most common unbalanced abnormalities
are deletions of 5q, monosomy 7, deletion of 7q, trisomy 8, deletion of 9q, trisomy 11,
trisomy 13, and trisomy 1.
About 10–20% of AML patients show so-called complex or aberrant karyotypes, which are associated
with a very poor prognosis. The definition of a complex karyotype varies among study groups.
It is most commonly defined as the presence of at least three cytogenetic abnormalities.
In approximately 45% of AML patients with aberrant karyotypes that have two or more karyotypic
abnormalities, one or more of these represents a secondary change. For example, in about 70–80% of
patients with t(8;21), additional aberrations are observed, the most common being the loss of a sex
chromosome. In addition, about 30–50% of patients with inv(16) show additional chromosome aberrations,
with trisomies of chromosomes 8, 21, or 22 being most frequently observed. The frequency