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Abnormal function of the bone marrow microenvironment in chronic
myelogenous leukemia: role of malignant stromal macrophages
R Bhatia, PB McGlave, GW Dewald, BR Blazar and CM Verfaillie
Department of Medicine, University of Minnesota, Minneapolis, USA.
The bone marrow microenvironment supports and regulates the proliferation
and differentiation of hematopoietic cells. Dysregulated hematopoiesis in
chronic myelogenous leukemia (CML) is caused, at least in part, by
abnormalities in CML hematopoietic progenitors leading to altered
interactions with the marrow microenvironment. The role of the
microenvironment itself in CML has not been well characterized. We examined
the capacity of CML stroma to support the growth of long-term
culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The
growth of normal LTC-IC on CML stroma was significantly reduced compared
with normal stroma. This did not appear to be related to abnormal
production of soluble factors by CML stroma because normal LTC- IC grew
equally well in Transwells above CML stroma as in Transwells above normal
stroma. In addition, CML and normal stromal supernatants contained similar
quantities of both growth-stimulatory (granulocyte colony-stimulating
factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF,
and interleukin-1 beta) and growth- inhibitory cytokines (transforming
growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor
necrosis factor-alpha). The relative proportion of different cell types in
CML and normal stroma was similar. However, polymerase chain reaction and
fluorescence in situ hybridization studies showed the presence of
bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages.
To assess the effect of these malignant macrophages on stromal function,
CML and normal stromal cells were separated by fluorescence-activated cell
sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+)
populations. CML and normal CD14- cells supported the growth of normal
LTC-IC equally well. However, the addition of CML macrophages to normal or
CML CD14- mesenchymal cells resulted in impaired progenitor support. This
finding indicates that the abnormal function of CML bone marrow stroma is
related to the presence of malignant macrophages. In contrast to normal
LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not
impaired and was significantly better than that of normal LTC-IC cocultured
with the same CML stromal layers. These studies demonstrate that, in
addition to abnormalities in CML progenitors themselves, abnormalities in
the CML marrow microenvironment related to the presence of malignant
stromal macrophages may contribute to the selective expansion of leukemic
progenitors and suppression of normal hematopoiesis in CML.
Volume 85,
Issue 12,
pp. 3636-3645,
06/15/1995
Copyright © 1995 by The American Society of Hematology
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