The effects of interferon‐α on the proliferation of CML progenitor cells in vitro are not related to the precise position of the M‐BCR breakpoint

Abstract

We investigated the effects of brief (2 h) and continuous exposure to recombinant interferon-alpha (2a) (rIFN-alpha) on the proliferation of primitive (blast colony-forming cells, Bl-CFC) and committed myeloid progenitor cells (BFU-E and GM-CFC) derived from blood and bone marrow of patients with chronic myeloid leukaemia (CML) and normal subjects. In all three clonogenic assays, rIFN-alpha suppressed colony formation in a dose-dependent manner. No differences were detected in the proliferation of CML or normal Bl-CFC and GM-CFC exposed to rIFN-alpha. Erythroid colony formation by normal, but not by CML BFU-E, was inhibited by relatively low concentrations (100 U/ml) of rIFN-alpha. However, in patients whose blood or marrow contained a mixture of Philadelphia chromosome (Ph)-positive and Ph-negative BFU-E, cytogenetic analysis of individual erythroid colonies showed no differential inhibition by rIFN-alpha. We found no difference in the sensitivity to rIFN-alpha of GM-CFC from patients whose leukaemic cells expressed BCR/ABL mRNA with the b2a2 junction and that of GM-CFC from patients with the b3a2 mRNA. We conclude that (1) rIFN-alpha does not have a significant leukaemia-specific effect on the progenitor cells detected in these assays, and (2) the sensitivity of CML GM-CFC to rIFN-alpha is independent of the type of BCR/ABL message present in the cells. The clinical efficacy of rIFN-alpha could be due to selective toxicity to cells not assayed in this study, to effects on accessory cells or to alterations induced in progenitor cell/stromal cell interactions.

Role of beta 1 and beta 2 integrins in the adhesion of human CD34hi stem cells to bone marrow stroma.

“…The influence of fibronectin on proliferation and differentiation of erythroid cells has been documented (75,76). Adhesion of CD4-CD8 -thymocytes to thymic stromal cells through FN-FN receptor interaction is known to be critical for their differentiation (77 Disruption ofnormal adhesion pathways between stem and stromal cells has been implicated as a critical factor in pathogenesis of chronic myeloid leukemia (81,82). Furthermore, after chemotherapy and/or total body irradiation, the observed extravascation of stem cells into peripheral blood (83) …”

Combination of interferon alpha with either Ara-C or ATRA in vitro reduces the selective action of interferon against CML CFU-GM

“…[8][9][10][11] However, we found that CML CFU-GM were more sensitive to Ara-C than were normal CFU-GM in the primary colony assay. This finding agrees with the results of Sokal et al 15,16 and suggests that Ara-C might provide therapeutic benefit as a result of preferential cytotoxicity against CML progenitor cells.…”

Treatment with interferon-alpha preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM.

“…However, the mechanism of this effect is not known. There is no substantial difference in the sensitivity of primary normal and CML clonogenic progenitor cells (granulocyte-macrophage colony-forming cells [CFU-GM] and erythroid burst-forming units [BFU-E]) to treatment with IFN-␣ in vitro (10)(11)(12)). An alternative explanation has been sought by postulating that the defective adhesion to bone marrow stromal cells that characterizes primitive hematopoietic progenitor cells in CML (13)(14)(15)) is reversed by IFN-␣ therapy, so that malignant progenitor cell proliferation can be controlled by inducing them to interact with the bone marrow microenvironment (16,17).…”