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Chronic myeloid leukemia
Pathology
The Philadelphia chromosome
The Ph1 results from a reciprocal translocation between the long
arms of chromosomes 9 and 22 t(9;22)(q34;q11) and is demonstrable in
all hematopoietic precursors. This in turn results in a fused
bcr-abl gene and in the production of an abnormal tyrosine kinase
protein that causes the disordered myelopoiesis found in CML.
- In chromosome 9: The c-abl proto-oncogene located in
chromosome 9q34 encodes for a nonreceptor protein-tyrosine
kinase expressed in most mammalian cells.
- In chromosome 22: The breakpoint occurs within the
BCR gene and usually involves an area known as the breakpoint
cluster region (bcr), located either between exons b3 and b4 or
between exons b2 and b3.
- The fusion: There are two different fusion genes can
be formed, both of them joining exon 2 of abl with either exon 2
(b2a2) or exon 3 of bcr (b3a2).
Upon translation, a new protein with a molecular weight of 210 kd
(p210BCR-ABL) is synthesized, which, compared to the normal c-abl,
has markedly increased kinase activity and can transform transfected
cells and induce leukemia in transgenic mice. The mechanism of
oncogenesis of p210BCR-ABL is unclear, but, upon phosphorylation, it
can activate several intracellular pathways, including ras and the
MAP kinase pathway, the Jak-Stat pathway, the PI3 kinase pathway,
and the myc pathway. Ultimately, this leads to altered adhesion to
extracellular matrix and stroma, constitutive activation of
mitogenic signals, and inhibition of apoptosis.
Philadelphia negative CML
Philadelphia negative CML differs from typical CML and
may be a different disease. The age profile is different with the
Philadelphia negative variety favoring young children and elderly
persons. The leucocyte and platelet counts tend to be lower. The
bone marrow tends to show more immature cells in the myeloid series.
The NAP score is higher. The prognosis of this type of CML is
poorer.
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Clonality
Clonal studies have demonstrated that CML is a clonal
disease of an abnormal stem cell. Myeloid, erythroid, megakaryocytic
and most lymphoid cells are involved in the malignant clone.
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