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Chromosomal Abnormalities In Chronic Myelogenous Leukemia

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Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a neoplastic disease of hematopoietic system characterized by a clonal proliferation of granulocyte precursors, without the loss of their differentiation capability. Therefore in peripheral blood exists an increased number of granulocytes and granulocyte precursors and an increased number of blast cells.

In its evolution, CML is passing through three phases: chronic, accelerated and blast crisis. Chronic phase of disease is characterized by mature cells proliferation. Accelerated phase of CML is characterized by the occurrence of new cytogenetic abnormalities, superimposed over the existing ones. Blast phase or blast crisis is characterized by a rapid proliferation of  immature cells.85% of patients are diagnosed in the chronic phase of the disease and then naturally progress to the accelerated phase and blast crisis in 3 to 5 years from diagnosis. The diagnosis of CML is based on the histopathologic examination of bone marrow and cytogenetic abnormalities in bone marrow cells.

Chronic myelogenous leukemia is a neoplastic disease of hematopoietic system caused by a single, specific genetic mutation. This mutation occurs in 90% of cases  and results from a cytogenetic aberration known as the Philadelphia chromosome (a translocation between chromosomes 9 and 22).

Cytogenetic analysis has a major importance in chronic myelogenous leukemia, because:

  • Can confirm the diagnosis of CML;
  • Can predict blast crisis;
  • Can assess disease prognosis;
  • Can assess the degree of remission.

Philadelphia Chromosome

Philadelphia chromosome was the first chromosome described as an aberrant chromosome in a malignant disorder by Nowel and Hungeford in 1960. After 10 years, Rowely found that the Philadelphia chromosome is not the result of a loss of genetic material (deletion of the long arm of chromosome 22), but the result of a reciprocal translocation between chromosomes 9 and 22. After another 10 years, it was demonstrated that after a chromosomal structural modification,  abl gene (Abelson murine leukemia) located on chromosome 9 is translocated on bcr gene (break point cluster region) located on chromosome 22 and form a hybrid gene called bcr / abl which encodes a protein kinase that plays an important role in leukemic cell clonal proliferation.

The breaking point of the bcr gene interests a short portion of the gene, unlike the breaking point of the abl gene that interests a longer portion of the gene and is located in different areas. Indirect evidence of these occurrences are represented by the fact that hybrid gene bcr / abl contains two types of messenger RNA and that this hybrid gene synthesizes two different proteins, P190 and P210.

Philadelphia Chromosome

Philadelphia Chromosome

Due to the fact that Philadelphia chromosome was identified both in chronic myelogenous leukemia and in acute leukemia, some authors propose that in cases where patients presented at the onset of the disease Philadelphia chromosome to be included in acute leukemia than chronic myelogenous leukemia, following that subsequent investigations to decide certainty about the diagnosis.

Although through classical cytogenetic methods, the Philadelphia chromosome is absent in approximately 10% of patients with CML, modern molecular genetic methods, especially polymerase chain reaction (PCR) and Southern blot method highlight this hybrid gene bcr / abl in 30% to 50% of these cases. High proportion of 95% -97% of cases of CML with positive Philadelphia chromosome highlights the major involvement of  bcr/abl gene in clonal proliferation of leukemia cells.

The presence of  Philadelphia chromosome shows a favorable prognosis, respectively patients survive about 3-4 years after diagnosis when conventional therapy is administrated or survival can be extended to 8-9 years if alpha-interferon is administrated. Furthermore, the advent of Gleevec (imatimib) extended survival rate and complete remission to a much longer periods of time.

In some cases of CML were found translocations between chromosome 17 and 22 or more complex translocations involving at least three chromosomes.

In about 5% of cases, besides Philadelphia positive cell population, there are cells with normal karyotype. This mosaicism dose not appear to have prognostic implications.

CML evolution is biphasic, with a chronic phase that has an average duration of 2-4 years, with positive Philadelphia chromosome, followed by an acute phase. Transition to the acute phase may be sudden or gradually through an accelerated phase. The appearance of accelerated phase may be announced by the occurrence of additional chromosomal changes:  Philadelphia chromosome duplications, chromosome 8 trisomy, the occurrence of isochromosome 17 and trisomy 19.

In the acute phase (blast crisis) can be seen diverse cell clones with different chromosomal abnormalities, characterized mainly by aneuploidy (changes in the number of cell chromosomes, there are normally 46 chromosomes).

The existence of correlations between chromosomal changes and their effect on phenotype provides indications regarding prognosis.