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Analysis of hematopoiesis in human normal long-term marrow cultures and in cultures from patients with CML and AML Coulombel, Laure


The hematopoietic system supplies short-lived functional end cells of multiple lineages from a common pool of pluripotent stem cells throughout life. In man neoplastic transformation of these stem cells results in the development of the acute and chronic myeloid leukemias. An in vitro system where functional murine stem cells can be maintained for several months has recently become available. This system has been a powerful tool to analyze mechanisms regulating normal hematopoiesis and leukemogenesis in mice. The purpose of this work was to develop an analogous culture system applicable to human marrow and to evaluate its ability to support leukemic hematopoiesis. Long-term cultures were established with normal human marrow cells. In these, the more primitive progenitors were found to be almost exclusively located in the adherent layer for the duration of the culture (i.e., at least 2 months). A prerequisite for these studies was the development of a procedure for detaching adherent cells so that various colony-forming progenitors could be assayed in semi-solid media. The consistent finding of adherent layer-associated hematopoiesis suggests that cell-cell interactions between primitive hematopoietic cells and adherent layer elements may be essential for the maintenance of the former. Long-term cultures were also initiated with marrow from 11 CML patients and 13 AML patients (all untreated) and maintenance of normal and neoplastic progenitor cell populations assessed. A common finding was the rapid disappearance of neoplastic progenitor cells (recognized either by the presence of chromosomal abnormalities or by their abnormal differentiation capacity) in most cultures, even though cytogenetically normal precursors were often maintained. These differences between the behaviour of normal and neoplastic cells in long-term cultures may reflect changes at the stem cell level that are related to the acquisition of abnormal growth properties. In a minority of patients a different result was obtained. Clonal dominance persisted in vitro and normal hematopoiesis was not detected. Thus long-term cultures have also allowed differences in the behaviour of primitive neoplastic cells from different patients to be revealed. Future investigation of the basis for these differences may provide new insights into the biological heterogeneity that characterizes these disorders

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