The Principles of Clinical Cytogenetics - Extra Materials - Springer

370 Rizwan Naeem
Table 1 (continued)
Langerhans cell sarcoma
Interdigitating dendritic cell sarcoma/tumor
Follicular dendritic cell sarcoma/tumor
Follicular dendritic cell sarcoma/tumor
Dendritic cell sarcoma, not otherwise specified
Mastocytosis
Cutaneous mastocytosis
Systemic mastocytis
Mast cell sarcoma
Extracutaneous mastocytoma
ages of 50 and 59 years (8). In most cases, it is a triphasic disorder, starting with the chronic phase
that, if left untreated, can proceed to a CML-accelerated phase and CML with blast crisis. This disorder
is mainly of hematopoietic tissue in origin, involving primarily the blood, bone marrow, spleen,
and liver, but during blast crisis, extramedullary tissues, including lymph nodes, skin, soft tissue, and
sometimes the central nervous system, can be involved. The most common presenting features of
CML are very mild to high white blood cell counts, fatigue, night sweats, and/or splenomegaly.
In the WHO classification, the diagnostic criterion for CML is the unequivocal presence of a “Philadelphia”
(Ph) rearrangement [t(9;22)(q34;q11.2), see Fig. 1t], involving the Breakpoint Cluster Region
and Ableson oncogenes (BCR and ABL1) (4,12). See also Fig. 9 of Chapter 17. Approximately 90–95%
of CML patients present with a Philadelphia rearrangement at the time of initial diagnosis. The presence
of this rearrangement has been seen in all lineages of maturing cells; therefore, this is a true multilineage
disease. The remaining 5–10% of CML cases without a classic Philadelphia rearrangement present in
varying forms, either involving other chromosomes (a complex rearrangement) or, in some cases, a
cryptic translocation involving BCR and ABL1. Therefore, the diagnostic criterion for CML is the unambiguous
presence of the BCR/ABL1 translocation transcript (13). Variant translocations could implicate
a third or fourth chromosome. Although the involvement of chromosome 9 or chromosome 22
might be hidden and at times the karyotype appears normal (“Ph-negative CML”), the hybrid BCR/
ABL1 gene is always present (otherwise, the disease is not CML). One of the proposed mechanisms of
CML leukemogenesis is that “accidents” arise in a bone marrow stem cell during mitosis, producing the
translocation between chromosomes 9 and 22, resulting in the BCR/ABL1 fusion gene.
The normal ABL1 gene is transcribed into an mRNA of 6–7 kb, which produces a 145-kDa protein
with tyrosine kinase activity. The hybrid BCR/ABL1 gene is transcribed into an mRNA of 8.5 kb,
which produces a protein of 210 kDa, with a subsequent increase in protein kinase activity and halflife.
In CML, the breakpoints in the BCR gene are almost always in the major breakpoint cluster
region or M-BCR, involving exons 12–16. This is also known as a B1/B5 translocation and results in
an abnormal chimeric protein known as p210, with increased tyrosine kinase activity. In a minority of
cases, the breakpoint in the BCR gene can occur in a minor region (m-BCR), in exons 17–20. This
translocation has also been known as translocation C1/C4, and in this case, an even larger chimeric
protein, p230, is produced. Interestingly, patients with the chimeric protein p230 usually demonstrate
prominent neutrophilic maturation. Another chimeric protein is noted in the minor breakpoint cluster
regions, which results from the translocation involving BCR exons 1 and 2 and produces a shorter
fusion protein, p190. This chimeric protein is most frequently associated with “Philadelphia-positive”
acute lymphoblastic leukemia. A small number of p190 chimeric proteins or gene products can be
detected in CML, which represents an alternative splicing mechanism in this disorder (14–16).
This fusion product or chimeric protein permanently activates tyrosine kinase that is freed from
normal regulation of its parent ABL1 kinase. The BCR/ABL1 fusion protein begins to excessively
phosphorylate multiple cellular proteins, resulting in an altered expression profile of the stem cell.