Identification and Characterization of Stem Cells in Preleukemia and Leukemia
Sammanfattning: Hematopoietic stem cells (HSCs) are responsible for the daily and life long production of large numbers of mature blood cells through highly regulated self-renewal and multilineage capabilities. Leukemias on the other hand, are characterized by a clonal, dysregulated, lineage skewed proliferation and impaired differentiation as the result of multiple accumulated genetic events. In acute myeloid leukemia (AML) most leukemic blasts have limited proliferative capacity and it has been shown that a small subpopulation of leukemic stem cells (LSCs) possess self-renewal and extensive proliferative capabilities and are thereby responsible and also sufficient for maintaining the leukemia. Myelodysplastic syndromes (MDS) and polycytemia vera (PCV) are myeloid preleukemic disorders thought to originate in a multipotent but myeloid restricted progenitor based on clonal involvement of erythroid, megakaryocytic, granulocytic but not lymphocytic cells. However, the lack of clonal involvement of mature lymphocytes does not exclude that MDS and PCV originate in normal HSCs, since the transformation events might be incompatible with development along the lymphoid pathway and the normal lymphocytes might rather be produced from residual normal HSCs or long-lived lymphoid progenitors produced prior to the onset of the disease. We have been able, through fluorescence activated cell sorting (FACS) purification, fluorescence in situ hybridization (FISH) clonal evaluation and functional HSC reconstitution assays, to show that MDS and PCV initiating cells have a CD34+CD38-Thy-1+ HSC phenotype, strongly indicating that MDS and PCV originates in normal HSCs. In MDS patients with 5q deletions, the origin in normal HSCs was further supported by multilineage involvement including B lymphoid progenitors and in one case also mature B cells. Acute lymphoblastic leukemia (ALL) with t(12;21) translocation have a fairly good prognosis, given only conventional chemotherapy while ALL with Philadelphia chromosome (Ph+) must be allogeneic stem cell transplanted to obtain cure. Using the same strategy as for MDS and PCV, we could for t(12;21) ALL establish that the CD34+CD38- candidate HSC pool could be subdivided into CD19+ leukemic stem cells and CD19- non-clonal, functionally intact normal HSCs while both populations were leukemic in Ph+ ALL. In addition, little or no residual normal HSC activity could be found in Ph+ ALL indicating that leukemias originating in the HSC compartment might negatively affect residual normal HSC activity, presenting one plausibel explanation for the differential prognosis in these two subgroups of ALL.
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