The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Hematologic Neoplasms 375
and 5q, and translocations and inversions of chromosome 3 involving bands q21 and q26.2 (see
Fig. 2aaa) have been reported (39,40). As ET is often a diagnosis of exclusion, the absence of a
Philadelphia rearrangement is necessary, as is the case with CNL.
MYELODYSPLASTIC/MYELOPROLIFERATIVE DISEASES
The myelodysplastic/myeloproliferative diseases (MDS/MPD) include chronic myelomonocytic leukemia,
atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia and “myelodysplastic/
myeloproliferative disease, unclassified.”
As the name indicates, this group includes cases with both dysplastic and proliferative morphology
at the time of presentation. These cases are difficult to assign to either the myelodysplastic or
myeloproliferative group. This category will be a focus of study of the molecular pathways involved
in the control of proliferation and abnormal maturation, and dysplasia. Most of the clinical and pathological
presentation is a result of the abnormal regulation of myeloid pathways or cellular proliferation.
These are multilineage disorders with mild clinical symptoms, because of the complication of
both cytopenia and nonfunctioning dysplastic cells.
At present, there have been no genetic defects identified that are specific to any of these entities.
There are some recurring chromosomal defects, but they are nonspecific and are seen in many similar
disorders. A high frequency of NRAS mutations have been reported in many MDS/MPD disorders,
suggesting deregulation of the RAS pathway (38). In chronic myelomonocytic leukemia (CMML)
and atypical CML (aCML), translocations [t(5;12)(q33;p13) and t(5;10)(q33;q22)] have been
reported, which result in fusions that enhance the tyrosine kinase activity of the receptor PDGFRβ.
This, in turn, leads to abnormal activation of the RAS pathway and other signal transduction pathways
(29,38). However, it is clear that this mechanism is not unique to these disorders.
Chronic Myelomonocytic Leukemia
Chronic myelomonocytic leukemia (CMML) is a clonal disorder of bone marrow stem cells
characterized by persistent monocytosis, less then 20% blasts, dysplasia, and the absence of a
Philadelphia rearrangement. In about 20–40% of cases, nonspecific clonal cytogenetic abnormalities
are found. The most frequently recurring abnormalities include trisomy 8, monosomy 7
or deletions of 7q (see Fig. 2h,i,j,k), and structural abnormalities involving chromosome 12p
(39–43). The WHO classification suggests that isolated cases of i(17)(q10) are a unique group
within the MDS/MPD, but many of these cases can be classified as CMML (see Fig. 2rr). In
addition, as many as 40% of cases show point mutations of RAS at the time of the diagnosis or
during the course of the disease (44).
Atypical Chronic Myeloid Leukemia
Atypical chronic myeloid leukemia (aCML) is a leukemic disorder that demonstrates both myeloproliferative
and dysplastic features at the time of initial presentation, hence it is included here. In
most cases, the leukocytosis predominantly involves immature and mature neutrophils with a definitively
dysplastic phenotype. In addition, multilineage dysplasia is commonly seen, thereby suggesting
the stem cell origin of this disorder.
One of the diagnostic features of this condition is the absolute absence of a Philadelphia rearrangement
or any evidence of a BCR/ABL1 fusion gene transcript. Clinically, most of the patients
present with anemia or sometimes with thrombocytopenia. The chief complaint is often splenomegaly
(45–47). In most cases, the white blood cell (WBC) count is variable, with values ranging from
35 × 109 to 96 × 109 cells/L. Blasts usually account for more than 5% and less than 20% of the
peripheral blood white cells. There is minimal or no absolute basophilia and less than 2% of the
WBCs are basophils. There is minimal or no absolute monocytosis and monocytes represent less
than 10% of WBCs. Bone marrow biopsy is usually hypercellular, with evidence of granulocytic