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The nature of chronic myelogenous leukaemia

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In common with other neoplasms, chronic myeloid or chronic myelogenous leukaemia (CML) can be viewed as an acquired genetic disease, resulting from genetic alteration in a haemopoietic stem cell that gives rise to an abnormal clone of cells, the behaviour of cells of this clone being responsible for the disease phenotype. In the case of CML the causative mutation occurs in a pluripotent lymphoid-myeloid stem cell (Fig. 2.1), thus creating the possibility of differentiation down various pathways in different phases of the disease. The specific genetic event responsible is a reciprocal balanced translocation between chromosome 9 and chromosome 22 (Fig. 2.2). Such a translocation has the potential to create two new fusion genes at the two sites where the chromosomal fragments rejoin. It is the BCR-ABL1 fusion gene on the derivative chromosome 22 (the Philadelphia chromosome) that is crucial for the development of the disease. Chronic myeloid leukaemia is viewed as one of the myeloproliferative neoplasms, a group of disorders characterized by effective proliferation of myeloid precursors with overproduction of end cells of at least one myeloid lineage. This condition is sometimes designated chronic granulocytic leukaemia, this term emphasising the differentiation to cells of all three granulocyte lineages.

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Figure 2.1

A diagram of the stem cell hierarchy and myeloid and lymphoid differentiation pathways. Abbreviation: NK, natural killer. The red arrow shows the level in the hierarchy at which the mutation occurs in chronic myeloid leukaemia.

Graphic Jump Location
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Figure 2.2

A diagram showing how the t(9;22)(q34;q11.2) leads to formation of the Philadelphia chromosome. Chromosome 9 breaks at 9q34 and chromosome 22 at 22q11.2 (red arrows). The distal parts of the two chromosomes are exchanged. The derivative chromosome 9, referred to as der(9), is composed mainly of chromosome 9 material but the end of its long arm has been replaced by a larger segment from the end of the long arm of chromosome 22. Similarly the derivative chromosome 22, referred to as der(22) or the Philadelphia (Ph) chromosome, is composed mainly of chromosome 22 material, but it has lost a significant part of its long arm, which has been replaced by a smaller segment from the long arm of chromosome 9. Because no chromosomal segment has been lost this is referred to as a balanced reciprocal translocation.

Graphic Jump Location
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Historical overview of the myeloproliferative neoplasms

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The concept of the myeloproliferative disorders (now known as myeloproliferative neoplasms) as a group of closely related disorders was formulated by William Dameshek in 1951 [1]. His editorial on this subject commenced with the words, 'With accumulating experience, it becomes more and more evident that the bone marrow cells - erythroblasts, granulocytes, megakaryocytes - often proliferate en masse or as a unit rather than as ...

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