PMID- 7780147
OWN - NLM
STAT- MEDLINE
DCOM- 19950720
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 85
IP  - 12
DP  - 1995 Jun 15
TI  - Abnormal function of the bone marrow microenvironment in chronic myelogenous 
      leukemia: role of malignant stromal macrophages.
PG  - 3636-45
AB  - 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.
FAU - Bhatia, R
AU  - Bhatia R
AD  - Department of Medicine, University of Minnesota, Minneapolis, USA.
FAU - McGlave, P B
AU  - McGlave PB
FAU - Dewald, G W
AU  - Dewald GW
FAU - Blazar, B R
AU  - Blazar BR
FAU - Verfaillie, C M
AU  - Verfaillie CM
LA  - eng
GR  - R01-CA-458401/CA/NCI NIH HHS/United States
GR  - R01-HL4993001/HL/NHLBI NIH HHS/United States
GR  - R01-HO5403901/HO/NHLBI NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antigens, CD)
RN  - 0 (Cytokines)
SB  - IM
MH  - Antigens, CD/biosynthesis
MH  - Bone Marrow/metabolism/*pathology
MH  - Cell Communication
MH  - Cell Division
MH  - Cytokines/biosynthesis
MH  - Hematopoietic Stem Cells/pathology
MH  - Humans
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism/*pathology
MH  - Macrophages/pathology
MH  - Stromal Cells/*pathology
MH  - Tumor Cells, Cultured
EDAT- 1995/06/15 00:00
MHDA- 1995/06/15 00:01
CRDT- 1995/06/15 00:00
PHST- 1995/06/15 00:00 [pubmed]
PHST- 1995/06/15 00:01 [medline]
PHST- 1995/06/15 00:00 [entrez]
AID - S0006-4971(20)79717-X [pii]
PST - ppublish
SO  - Blood. 1995 Jun 15;85(12):3636-45.