Recombinant hematopoietic growth factors fail to induce a proliferative response in precursor B acute lymphoblastic leukemia.
We have tested a panel of recombinant hematopoietic growth factors (HGF) including the interleukins (IL) 1, 2, 3, 4, and 6 and the colony stimulating factors GM-CSF, G-CSF, M-CSF for their ability to induce proliferation of precursor B acute lymphoblastic leukemia cells (ALL) from 19 patients. In Ficoll-Isopaque isolated and T cell-depleted ALL bone marrow samples, IL2 (two cases), IL3 (four cases), and GM-CSF (one case) infrequently stimulated DNA synthesis measured by 3H-thymidine (TdR) uptake, and the other recombinant growth factors completely failed to do so. In repeat experiments with ALL blasts purified by fluorescence activated cell sorting (FACS), IL2, IL3, and GM-CSF responses could not be reproduced, suggesting that nonleukemic contaminant cells, and not the ALL blasts, had been stimulated by these factors. Cocktails containing combinations of IL1-IL4 and IL6 also lacked proliferation inducing potency. Depending on the purity of the incubated ALL cell samples, an impure preparation of B cell growth factors that has been reported to contain a highly effective stimulatory activity for precursor B ALL cells induced proliferation of residual normal cells as well as the ALL cells, as was evident from combined analysis of DNA synthesis and karyotyping. Exposure of the ALL blasts to artificial activators of protein kinase C and Ca2+ mobilization resulted in significant rises in 3H-TdR uptake, suggesting that these intracellular compounds are involved in transducing signals that upregulate proliferation. Although it remains possible that some of the human recombinant growth factors promote the growth of precursor B ALL cells in combination with other stimuli, a dominant role in the regulation of proliferation of these cells cannot be attributed to any of these cytokines at the present time.
Touw
I
I
Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Groot-Loonen
J
J
Broeders
L
L
van Agthoven
T
T
Hählen
K
K
Hagemeijer
A
A
Löwenberg
B
B
D001402:B-Lymphocytes; D000001:Calcimycin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D006801:Humans; D015847:Interleukin-4; D007378:Interleukins / Q000494:pharmacology*; D007945:Leukemia, Lymphoid / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003115:Colony-Stimulating Factors; D007378:Interleukins; D011994:Recombinant Proteins; D015847:Interleukin-4; D000001:Calcimycin; D013755:Tetradecanoylphorbol Acetate