Heterogeneous mechanisms of autocrine growth of AML blasts

The ability of blast cells to grow autonomously and to produce autostimulatory growth factors has been investigated in 25 consecutive patients with AML. An autostimulatory index (ASI) was calculated (no. of colonies without CSF divided by no. of colonies with CSF) and patients classified into four groups: Group 1 (n = 3): non-growers; Group 2 (n = 4): CSF-dependent (ASI less than 0.1); Group 3 (n = 11): partially autonomous (ASI 0.1-0.8); and Group 4 (n = 7): fully autonomous/CSF-unresponsive (ASI greater than 0.8). In Group 3 patients colony formation and DNA synthesis were significantly (P less than 0.01) augmented by CSFs but at high cell concentrations became CSF-independent. Blast cell-conditioned medium (BCCM) from these patients exhibited potent autostimulatory activity, increasing DNA synthesis by less than or equal to 5-fold, and also stimulated CSF-dependent homologous blasts by less than or equal to 20-fold. In 5/5 this activity was neutralized by anti-GM-CSF, which also inhibited autonomous proliferation of their blast cells. Group 4 blasts also secreted GM-CSF but their BCCM possessed no autostimulatory activity, and anti GM-CSF failed to inhibit their autonomous growth. No membrane-associated CSF activity was found, however purified cytosolic fractions stimulated proliferation of CSF-dependent homologous blasts, consistent with production and secretion of CSF which is present in active form in the cytosol but does not autostimulate via membrane receptors. These results suggest that autocrine mechanisms are important in regulating blast cell proliferation, but that the mechanisms are heterogeneous.