Potential Mechanisms of Action of Interferon-αin CML

Abstract

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.

A retrospective single centre study of the outcome of five different therapy approaches in 48 patients with relapse of chronic myelogenous leukemia after allogeneic bone marrow transplantation

“…In the latter patient group, augibility antigens and of activating lymphocytes mediating antigen-specific and nonspecific cytotoxicity. [36][37][38][39][40][41] Furthermentation of the GVL effect induced by DLT may therefore be necessary. more, in vitro activities of IFN-␣ on hematopoietic progenitor and marrow stroma cells include growth inhibition, A second transplant with unmanipulated marrow was given to six patients (two CP, two AP, two BC), who did modulation of adhesion molecule expression, and release of growth-regulating cytokines and receptors.…”

“…more, in vitro activities of IFN-␣ on hematopoietic progenitor and marrow stroma cells include growth inhibition, A second transplant with unmanipulated marrow was given to six patients (two CP, two AP, two BC), who did modulation of adhesion molecule expression, and release of growth-regulating cytokines and receptors. [39][40][41][42] not respond to various treatment approaches, including DLT, IFN-␣, and CTX. Two of six patients with advanced The use of donor leukocyte transfusions has been reported to be effective in the treatment of relapsed CML stage disease recurrence were transplanted with allogeneic peripheral blood progenitor cells.…”

Effect of Bcr sequences on the cellular function of the Bcr-Abl oncoprotein

“…Insight into the disease mechanism has come from studies of CML patient samples in long term bone marrow cultures. These studies have uncovered a CML-defect, that is the apparent reduction in the adhesiveness of the CML stem cells to the stromal layer (Dowding et al, 1991;Verfaillie et al, 1992). Interestingly, the reduced adhesion can be corrected by treatment with interferon-alpha, and this is correlated with the remission of the disease (Dowding et al, 1991;Bhatia et al, 1994Bhatia et al, 1995.…”

“…These studies have uncovered a CML-defect, that is the apparent reduction in the adhesiveness of the CML stem cells to the stromal layer (Dowding et al, 1991;Verfaillie et al, 1992). Interestingly, the reduced adhesion can be corrected by treatment with interferon-alpha, and this is correlated with the remission of the disease (Dowding et al, 1991;Bhatia et al, 1994Bhatia et al, 1995. The reduced adhesiveness may provide the CML stem cells with a growth advantage in the bone marrow microenvironment to allow the expansion of the Ph1-positive cells in the hematopoietic compartments (Dowding et al, 1991;Verfaillie, 1992).…”

GM-CSF can improve the cytogenetic response obtained with interferon-alpha therapy in patients with chronic myelogenous leukemia

“…Although the mechanism of action of IFN-A in CML is not known, stimulation of immune mechanisms has been advocated as one possibility. 16 Although in most patients who achieve complete cytogenetic remission BCR/ABL may still be detectable by PCR, in some, BCR/ABL eventually becomes undetectable. Still, clonogenic assays can demonstrate persistence of BCR/ABL-positive cells in patients with BCR/ABL-negative disease by RT-PCR.…”