Monocyte-macrophage-derived acidic isoferritins: normal feedback regulators of granulocyte-macrophage progenitor cells in vitro

Abstract

The recent identification of a leukemia-associated inhibitory activity (LIA) against granulocyte-macrophage progenitor cells (CFU-GM) as acidic isoferritins has now led to detection of this activity in normal bone marrow and blood cells. Detection of this activity depends on stimulation of CFU-GM by granulocyte-macrophage colony stimulatory factors (GM-CSF), and some conditioned media (CM) sources of GM-CSF (human placental and monocyte, mouse macrophage and WEHI-3) contained low levels of acidic isoferritin that lowered colony formation. Inactivation or removal of this activity increased the stimulatory capacity of the CM. CM depleted of acidic isoferritins or CM originally devoid of this activity (human GCT, 5637, Mo, lymphocytes: mouse L cells or pokeweed-mitogen-stimulated spleen cells) increased the sensitivity of the assay to detect acidic isoferritin inhibitory activity. This activity was selectively contained and released from normal monocytes and macrophages. Restriction of this activity to mononuclear phagocytes was substantiated, as only continuous cell lines of monocytes and macrophages or lines capable of induction to this lineage contained and released acidic isoferritin inhibitory activity. The cells of origin and target cells of action suggest that acidic isoferritin-inhibitory activity can be considered as a negative feedback regulator, at least in vitro.

Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

“…38 Macrophages activated by an aberrant inflammatory response are likely the main source of serum ferritin overproduction in AML patients. 16 However, it is not excluded that leukemic cells themselves could also contribute to serum ferritin elevation since a significant association was found between ferritin levels and leukocytosis (ie, tumor burden). Although our in vitro data are preliminary, it is plausible that AML cells could release ferritin in the extracellular media.…”

“…Although the cellular origin of ferritin is thought to reside in the mononuclear phagocyte system and hepatocytes, the precise source of serum ferritin in human hematological malignancies has yet to be determined. [16][17][18] We took advantage of publicly available transcriptomic databases to assess the expression of FTH1 and FTL in AML and normal HSC. Analysis of the bloodspot database and of the functionally defined leukemic stem cell (LSC)-specific signature showed that FTH1 and FTL were overexpressed in AML cells and LSC compared with normal HSC (Figure 3A-B).…”

Prenatal identification of potential donors for umbilical cord blood transplantation for Fanconi anemia

“…For CFU-GM assays, cord blood cells were plated in 0.3 percent agar culture medium in the presence of 10 percent (vol/ vol) medium conditioned by the human cell line 5637 (5637CM, a source of colony-stimulating factors) as described elsewhere. 28 We counted colonies (>40 cells/aggregate) and clusters (3-40 cells/aggregate) containing granulocytes and/or macrophages after 14 days of incubation (5% C02, 5% 02, humidified conditions). We also plated cells to assay colonies deriving from CFU-GM, BFU-E, and CFU-GEMM in methylcellulose culture medium in the presence of 1 unit of erythropoietin (Toyoba New York, Inc., New York, NY) and 10 percent (vol/vol) 5637CM, as described elsewhere.29 Colonies forming in methylcellulose were also scored after 14 days of incubation under the same conditions as agar cultures.…”

Feedback regulators in normal and tumour tissues

“…Although indirect in its action, EPO is produced by the kidney in inverse proportion to the oxygen tension developed there by the red cell mass. Lactoferrin and acidic isoferritins have been implicated as further feedback regulators of GM-CFC growth and development (Broxmeyer et al 1978(Broxmeyer et al , 1982. Elaborated by the mature granulocyte macrophage populations, they are reported to block the production of the appropriate colony-stimulating factors for GM-CFC development.…”