Potential mechanisms of action of interferon-alpha in CML.
Treatment with interferon-alpha (IFN-alpha) adequately controls the leukemic cell mass in the majority of newly diagnosed patients with chronic myeloid leukemia (CML). However, the degree of response ranges from no 'hematologic' response to complete suppression of the leukemic clone. The mechanism(s) by which IFN-alpha elicits these responses is unknown, but in vitro studies have indicated that IFN-alpha might function by (1) selective toxicity against the leukemic clone, (2) enhancement of 'immune' regulation, and (3) modulation of bone marrow microenvironmental regulation of hematopoiesis. Using in vitro clonogenic assays we were unable to demonstrate that IFN-alpha selectively inhibited the proliferation of CML progenitor cells. We also found no difference in the expression of LFA-3 on normal or CML CD34+ cells. However, by panning and co-culturing hematopoietic cells on monolayers of bone marrow stromal cells, grown with and without IFN-alpha, we found that IFN-alpha enhanced the adhesion of CML progenitors to stromal cells, whereas adhesion by normal progenitor cells was essentially unaffected. This enhanced adhesion by CML progenitor cells was associated with a reduction in neuraminic acid levels in the extracellular matrix overlying stromal cells. Therefore, it is possible that one of the mechanisms by which IFN-alpha exerts its regulatory effect on the leukemic clone is through enhancement of hematopoietic cell-microenvironmental cell interactions.
Dowding
C
C
MRC/LRF Leukaemia Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Gordon
M
M
Guo
A P
AP
Maison
D
D
Osterholz
J
J
Siczkowski
M
M
Goldman
J
J
D015703:Antigens, CD / Q000096:biosynthesis; D018952:Antigens, CD34; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D018968:CD58 Antigens; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D003238:Connective Tissue / Q000187:drug effects; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006025:Glycosaminoglycans / Q000096:biosynthesis; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009438:Neuraminic Acids / Q000378:metabolism; D014410:Tumor Stem Cell Assay
D015703:Antigens, CD; D018952:Antigens, CD34; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules; D006025:Glycosaminoglycans; D007155:Immunologic Factors; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009438:Neuraminic Acids