GM-CSF stimulates proliferation of clonal leukemic bone marrow cells in acute myeloid leukemia (AML) in vitro

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to stimulate granulocytes, monocytes, and macrophages. We studied the effect of GM-CSF on (clonal) bone marrow (BM) cells obtained from AML patients after 7 days of culture in vitro: BM samples were obtained from 19 AML patients at diagnosis (DIA), from two patients with persisting disease (PERS), from eight patients in complete remission (CR), and from 12 healthy donors. Flow-cytometric comparison of differentiated, CD 15-positive cells or of CD34-positive blast cells before and after cultivation showed that the proportion of CD15-positive cells was increased in nine of 12 healthy BM samples, in 14 of 19 cases at DIA, in one of three cases during PERS, and in five of six cases in CR of AML. The proportion of CD34-positive cells was increased in one of 12 healthy BM samples, in seven of 19 cases at DIA, in one of two cases during PERS, and in three of seven cases in CR of AML. Southern blot analysis (SBA) performed in six cases during the course of AML, before and after cell culture, showed that clonal DNA increased after GM-CSF treatment in three of five cases studied at DIA, in six of nine cases studied in CR, in the one case studied at PERS, and in the one studied at relapse (REL). In one case of trisomy 8 at DIA a normal karyotype was demonstrated in CR. However, after 7 days of cultivation of the cells in GM-CSF the trisomy 8 was detected in two of 17 metaphases isolated from colony-cells from methylcellulose cultures. Our data show that a 7-day treatment of BM cells with GM-CSF induced a differentiation of healthy and leukemic BM cells in the great majority of cases. An enrichment of CD34-positive cells was not achieved in healthy BM samples. However, in 70% of the cases in CR and in 30% of the cases at DIA of AML, clonal CD34-positive cells were enriched. This means that GM-CSF stimulates ('primes') leukemic cell growth in vitro.

Expression and prognostic value of hemopoietic cytokine receptors in acute myeloid leukemia (AML): implications for future therapeutical strategies

“…The effect of GM‐CSF and G‐CSF on blasts is used to sensitize them against chemotherapy (reviewed in 2). Several functional in vitro tests of others and us showed, that leukemic blasts proliferate after GM‐CSF‐stimulation (39, 40) or G‐CSF‐stimulation (41). Although most of the published in vivo studies did not demonstrate beneficial clinical effects of priming with G‐ or GM‐CSF, this does not rule out, that certain subtypes of AML could benefit from priming therapies.…”

Modulatory Effect of Dopamine on Doxorubicin-induced Myelosuppression

“…G-CSF has been shown to damage the self-renewal capacity after multiple courses of cytotoxic drugs (Van Os et al 1998), and HGFs also stimulate growth of a variety of non-haematopoietic cells, either normal (Dedhar et al 1988) or neoplastic (Sagawa et al 1991;Lopez-Marure et al 1998). In addition, GM-CSF stimulates proliferation of leukaemic bone marrow cells (Schmetzer et al 1999). Hence, simultaneous proliferation of haematopoietic progenitors and tumour cells could not be ruled out in tumourbearing subjects receiving HGFs.…”

Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia

“…However, GM-CSF has dual effects on blasts, which must be carefully considered. GM-CSF induces both proand anti-apoptotic signals and can be a stimulator of AML blast proliferation [55]. In different tumor models, GM-CSF has been shown to be either pro-or anti-tumoral, pro-or anti-angiogenic, all of which can depend on the microenvironment or directly on GM-CSF dosage [56].…”