Interferon-alpha overrides the deficient adhesion of chronic myeloid leukemia primitive progenitor cells to bone marrow stromal cells

Abstract

Primitive blast colony-forming cells (BI-CFC) from chronic myeloid leukemia (CML) patients are defective in their attachment to bone marrow-derived stromal cells compared with normal BI-CFC. We investigated the effect of recombinant interferon-alpha 2a (IFN-alpha) on this interaction between hematopoietic progenitor cells and bone marrow-derived stromal cells by culturing normal stromal cells with IFN- alpha (50 to 5,000 U/mL). At 50 U/mL we found that: (1) the capacity of stromal cells to bind two types of CML primitive progenitor cells (BI- CFC and long-term culture-initiating cells) was increased; and (2) the amount of sulfated glycosaminoglycans (GAGs) in the stromal layer was increased. However, sulfated GAGs were not directly involved in binding CML BI-CFC, unlike binding by normal BI-CFC, which is sulfated GAG- dependent. Neuraminidase-treated control stromal cells bound an increased number of CML BI-CFC, reproducing the effect of IFN-alpha, whereas the binding to IFN-alpha-treated stromal cells was unaffected by neuraminidase treatment. Thus, the enhanced attachment by primitive CML progenitor cells to INF-alpha-treated stromal cells might be due to changes in the neuraminic acid composition in the stromal cell layer. Our in vitro evidence may provide insights into the mechanism of action of IFN-alpha in vivo. Prolonged administration may alter the marrow microenvironment in some patients such that it can restrain the aberrant proliferation of Philadelphia chromosome (Ph)-positive stem cells while permitting Ph-negative stem cells to function normally.

Chronic Myeloid Leukemia Patients in Prolonged Remission following Interferon-α Monotherapy Have Distinct Cytokine and Oligoclonal Lymphocyte Profile

“…The mechanism of action of IFN-α therapy is incompletely understood; the drug exerts both direct cytostatic and immunomodulatory effects on leukemic cells. It can down-regulate the expression of the BCR-ABL1 gene, and activate several transcriptional factors that regulate cell proliferation, maturation, and apoptosis [13] , [14] , [15] , [16] , [17] . IFN-α can also induce recognition and elimination of CML cells by the immune system [18] , [19] , [20] , [21] .…”

Differential effect of interferon α on chronic myelogenous leukaemia and normal haematopoietic progenitors in a stromal cell co‐culture context: role of the flt3 ligand

“…In CML patients, IFN-a induces haematological remissions with emergence of Ph± haematopoiesis, suggesting that it has a differential impact on normal and leukaemic cells (Talpaz et al, 1986;Kantarjian et al, 1996;Guilhot et al, 1997). There is evidence for an indirect regulatory action of IFN-a on HPCs through the bone marrow microenvironment and this stroma-mediated regulation may differentially affect normal and CML cells, as was shown for integrinmediated adhesive or proliferative events (Dowding et al, 1991b;Upadhyaya et al, 1991;Bhatia et al, 1994Bhatia et al, , 1996 or immunologically based mechanisms (Selleri et al, 1997). The regulation of the production of cytokines by the bone marrow microenvironment could also be an important way through which IFN-a differentially controls normal and CML HPC growth.…”

“…Apart from its direct effects, differential effects of IFN-a could result from its action through the bone marrow microenvironment. IFN-a restores the defective adhesion of CML HPCs to the bone marrow stromal cells through integrins (Dowding et al, 1991b;Upadhyaya et al, 1991;Bhatia et al, 1994), the integrin-dependent regulation of proliferation (Bhatia et al, 1996) or the immunological control of the leukaemic clone (Selleri et al, 1997). Regulation of the cytokine production by bone marrow stromal cells may also be of importance in understanding the effects of IFN-a in CML.…”