COMPOSITION AND FUNCTION OF THE HEMATOPOIETIC MICROENVIRONMENT IN HUMAN MYELOID-LEUKEMIA

In normal adult mammals, blood cell production, hemopoiesis, takes pla ce within the medullary cavity. There, hemopoietic cell proliferation and differentiation are regulated by a network of stromal/accessory ce lls and their products tie cytokines and extracellular matrix molecule s), known as the hemopoietic microenvironment. Recent in vitro studies indicate that both cell composition and functional abnormalities of t he hemopoietic microenvironment are present in a proportion of patient s with myeloid leukemia, both chronic (CML) and acute (AML). Cell comp osition abnormalities have been primarily observed in a subset of pati ents with AML; these abnormalities include reduced numbers of fibrobla st progenitors and, in some cases, reduced numbers of macrophages and adipocytes. In terms of function, it has been shown that the marrow st romal cells from a significant number of both CML and AML patients, po ssess a deficient hemopoietic supportive capacity in vitro. This seems to be related to the presence of functionally abnormal, malignant mac rophages. The mechanisms by which these macrophages alter the hemopoie tic function of the marrow stroma, as a whole, are still not fully und erstood. Whereas in AML, a macrophage-derived soluble inhibitory activ ity (containing tumor necrosis factor alpha) has been described; in CM L, a direct, macrophage-mediated cell-to-cell contact mechanism for he mopoietic inhibition seems to be involved. To date, however, it is not clear whether the abnormalities in the hemopoietic microenvironment a re secondary to myeloid leukemia or if they precede clinical CML/AML. Furthermore, it is not known to what extent the functional abnormaliti es observed in vitro contribute to the hematologic dysfunction that ch aracterizes myeloid leukemia and to the in vivo progression of the dis ease.