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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3973-3982
Effects of the Tyrosine Kinase Inhibitor AG957 and an Anti-Fas Receptor
Antibody on CD34+ Chronic Myelogenous Leukemia Progenitor
Cells
Carmelo Carlo-Stella,
Ester Regazzi,
Gabriella Sammarelli,
Simona Colla,
Daniela Garau,
Aviv Gazit,
Barbara Savoldo,
Daniela Cilloni,
Antonio Tabilio,
Alexander Levitzki, and
Vittorio Rizzoli
From the Department of Hematology, University of Parma, Parma, Italy;
the Department of Biological Chemistry, The Hebrew University of
Jerusalem, Jerusalem, Israel; and the Department of Hematology,
University of Perugia, Perugia, Italy.
The hallmark of chronic myelogenous leukemia (CML) is the
Philadelphia (Ph) chromosome that fuses genetic sequences of the BCR
gene on chromosome 22 with c-ABL sequences translocated from chromosome
9. BCR/ABL fusion proteins have a dysregulated protein tyrosine kinase
(PTK) activity exerting a key role in malignant transformation.
Targeting the tyrosine kinase activity of BCR/ABL or using agents
capable of triggering apoptosis might represent attractive therapeutic
approaches for ex vivo purging. AG957, a member of the tyrphostin
compounds, exerts a selective inhibition of p210BCR/ABL
tyrosine phosphorylation. We report here that preincubation of CML or
normal CD34+ cells with graded concentration of AG957 (1 to 100 µmol/L) resulted in a statistically significant,
dose-dependent suppression of colony growth from multipotent,
erythroid, and granulocyte-macrophage progenitors as well as the more
primitive long-term culture-initiating cells (LTC-IC).
However, AG957 doses causing 50% inhibition (ID50) of CML
and normal progenitors were significantly different for multilineage
colony-forming units (CFU-Mix; 12 v 64 µmol/L; P = .008), burst-forming unit-erythroid (BFU-E; 29 v 89 µmol/L; P = .004), colony-forming unit-granulocyte-macrophage
(CFU-GM; 34 v 85 µmol/L; P = .004),
and LTC-IC (43 v 181 µmol/L; P = .004). In 5 of 10 patients, analysis of BCR/ABL mRNA on single progenitors by
reverse transcription-polymerase chain reaction showed that AG957 at 50 µmol/L significantly reduced the mean (±SD) percentage of
BCR/ABL-positive progenitors (92% ± 10% v 33 ± 5%;
P = .001). Because AG957 treatment resulted in
significantly higher percentages of apoptotic cells (30% v
9%) in the BCR/ABL-transfected 32DLG7 cells as compared with 32D-T2/93
cells (BCR/ABL-negative), we investigated the combined effects of AG957
with the anti-Fas receptor (Fas-R) monoclonal antibody CH11 that
triggers apoptosis. As compared with AG957 alone, the sequential
treatment of CML CD34+ cells with AG957 (1 µmol/L) and
CH11 (1 µg/mL) increased CFU-Mix, BFU-E, and CFU-GM growth inhibition
by 1.6-fold, 3-fold, and 4-fold, respectively. In contrast, the
treatment of normal CD34+ cells with AG957 and CH11
failed to enhance AG957-induced colony growth inhibition. We conclude
that (1) AG957 inhibits in a dose-dependent manner CML CD34-derived
colony formation by both primitive LTC-IC as well as committed CFU-Mix,
BFU-E, and CFU-GM; (2) this growth inhibition is associated with the
selection of a substantial amount of BCR/ABL-negative progenitors; and
(3) the antiproliferative effect of AG957 is dramatically increased by
combining this compound with the anti-Fas-R antibody CH11. These data
may have significant therapeutic applications.
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