Normal and leukemic hematopoiesis: Are leukemias a stem cell disorder or a reacquisition of stem cell characteristics?

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   Fig. 1.

   Hematopoietic and progenitor cell lineages. HSCs can be divided into LT-HSCs, highly self-renewing cells that reconstitute an animal for its entire life span, or ST-HSCs, which reconstitute the animal for a limited period. ST-HSCs differentiate into MPPs, which do not or briefly self-renew, and have the ability to differentiate into oligolineage-restricted progenitors that ultimately give rise to differentiated progeny through functionally irreversible maturation steps. The CLPs give rise to T lymphocytes, B lymphocytes, and natural killer (NK) cells. The CMPs give rise to GMPs, which then differentiate into monocytes/macrophages and granulocytes, and to megakaryotic/erythroid progenitors (MEP), which produce megakaryocytes/platelets and erythrocytes. Both CMPs and CLPs can give rise to dendritic cells. All of these stem and progenitor populations are separable as pure populations by using cell surface markers.

   
   
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   Fig. 2.

   Origin of the LSC. A given leukemia can be viewed as a newly formed abnormal hematopoietic tissue initiated by a few LSCs that undergo an aberrant and poorly regulated process of organogenesis analogous to that of normal HSCs. LSCs can either be HSCs, which have become leukemic as the result of accumulated mutations, or more restricted progenitors, which have reacquired the stem cell capability of self-renewal. Regardless of their origin, both types of LSCs give rise to similar end-stage leukemias.

   
   
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   Fig. 3.

   Deregulated pathways leading to leukemia. Although leukemias are heterogeneous in terms of phenotypes, there are general mechanisms underlying leukemic transformation such as increased cell survival, increased proliferation capacity, increased self-renewal capacity, genomic instability, and prevention of differentiation. Examples of such deregulated mechanisms and/or signaling pathways that have been found in various types of leukemias are indicated.