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Leukemic B-cell precursors express functional receptors for human
interleukin-3
FM Uckun, TG Gesner, CW Song, DE Myers and A Mufson
Department of Therapeutic Radiology-Radiation, University of Minnesota
Health Sciences Center, Minneapolis 55455.
The purpose of this study was to analyze the expression of functional
interleukin-3 (IL-3) receptors on leukemic B-cell precursors (BCPs) from 12
BCP acute lymphoblastic leukemia (ALL) patients and five BCP ALL cell
lines. The specific binding of biosynthetically labeled 35S- recombinant
(r) IL-3 to freshly obtained leukemic marrow blasts was initially
investigated. In five of 12 BCP ALL cases, the binding of 35S- rIL-3 was
markedly blocked by excess cold rIL-3, and the percentage of inhibitable
binding ranged from 53% to 78% (mean +/- SE = 65% +/- 4%). In these cases,
the cell-bound radioactivity ranged from 146 cpm/10(7) cells to 1,433
cpm/10(7) cells (mean +/- SE = 627 +/- 250 cpm/10(7) cells), indicating
that 1 to 14 femtomole (mean +/- SE = 6 +/- 2 fms) of [35S]rIL-3/10(7)
cells were specifically bound (= 60 to 840 molecules per cell). rIL-3
stimulated the proliferative activity of leukemic BCPs in a dose-dependent
fashion without inducing differentiation, and the half-maximal stimulatory
activity was observed at a concentration of 17 to 34 pmol/L.
Fluorescence-activated cell sorter (FACS)-isolated virtually pure
populations of CD10+CD19+ leukemic BCPs from two BCP ALL patients, as well
as from two of five BCP ALL cell lines, showed a marked proliferative
response to highly purified rIL-3, providing formal evidence that the
observed IL-3 responses were not mediated by accessory cells. There was a
high correlation between [35S]rIL-3 binding and proliferative response in
colony assays, indicating that functional IL-3 receptors were detected in
ligand binding assays. Scatchard plot analysis of the specific equilibrium
binding data for IL-3-responsive leukemic BCPs from one BCP ALL patient and
two BCP ALL cell lines yielded a straight linear regression line,
indicating the existence of a single class of 60 to 210 high-affinity IL-3
binding sites/cell. The calculated apparent affinity constant (Ka) values
ranged from 3.6 x 10(9) to 5.9 x 10(9) mol/L-1. Hence, the concentration of
IL-3 required to produce 50% maximal receptor occupancy (Kd) was in the
range of 168 to 280 pmol/L. These concentrations are approximately tenfold
higher than those required to induce 50% maximal proliferative response
from leukemic BCPs in colony assays, indicating that low receptor occupancy
is sufficient for growth stimulation of leukemic BCPs by rIL-3. In
comparison, less than 10 to 20 IL-3 molecules/cell were bound to IL-3
unresponsive leukemic BCPs even when the concentration of free-[35S]rIL- 3
was as high as 2 nmol/L.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 73,
Issue 2,
pp. 533-542,
02/01/1989
Copyright © 1989 by The American Society of Hematology
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