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Normal haemopoiesis

In the adult, normal haemopoiesis occurs predominantly in the bone marrow, although haemopoietic stem cells circulate in the blood stream and the potential for haemopoiesis in liver, spleen or other tissues is retained. All blood cells are derived ultimately from a pluripotent haemopoietic stem cell, able to give rise to lymphoid and myeloid lineages [1]. The pluripotent stem cells are capable not only of self renewal but also of generating multipotent myeloid stem cells and the common lymphoid stem cells (Figure 1.1). The multipotent stem cell gives rise in turn to committed progenitor cells from which cells of the major myeloid lineages are derived. Differentiation and maturation are controlled by a variety of cytokines which are to some extent specific for particular cell lines. In addition, the microenvironment and accessory cells such as fibroblasts and fat cells have a role in the differentiation and maturation of stem cells. Cells of haemopoietic origin include mast cells and osteoclasts.

Figure 1.1

A diagram of the stem cell hierarchy and myeloid and lymphoid differentiation pathways. Abbreviation: NK, natural killer.

Myeloid neoplasms arise from mutation in a haemopoietic stem cell or progenitor cell (Figure 1.2). Many neoplasms, including most types of acute myeloid leukaemia (AML) and the myelodysplastic syndromes (MDS) arise from a mutated multipotent stem cell. Some chronic myeloid leukaemias arise from mutation in a pluripotent stem cell so that at one stage of the disease the leukaemia may manifest itself as a lymphoid leukaemia or lymphoma. This is true of Philadelphia (Ph)-positive chronic myeloid leukaemia associated with a BCR-ABL1 fusion gene (in which B-lineage and less often T-lineage blast transformation can occur) and of FGFR1-related neoplasms, which at various stages of the disease may be manifest as chronic eosinophilic leukaemia, T-lineage lymphoblastic leukaemia/lymphoma, B-lineage lymphoblastic leukaemia/lymphoma or AML. It is possible that some subtypes of AML arise in a mutated committed progenitor cell without the capacity to differentiate into cells of erythroid or megakaryocyte lineages.

Figure 1.2

A diagram of the stem cell hierarchy and myeloid differentiation pathways showing the cell in which the causative mutation appears to occur in various haematological neoplasms. Abbreviations: AML acute myeloid leukaemia; CML chronic myeloid leukaemia; MDS myelodysplastic syndrome(s); MPD myeloproliferative disorder(s).

The molecular basis of haematological neoplasms

In common with other neoplasms, haematological neoplasms can be viewed as acquired genetic diseases in the sense that they result from genetic alteration in a stem cell that gives rise to an abnormal clone of cells, the behaviour of which is responsible for the disease phenotype. The host immune response also has a role in disease development since the body's immune response includes some ability to recognize tumour cells and destroy them.

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