Interleukin-3 protects Bcr-Abl-transformed hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors.
Bcr-Abl tyrosine kinase has been validated as a molecular target for the treatment of chronic myelogenous leukemia (CML). More recently, it has been reported that CML patients could develop resistance to the Bcr-Abl tyrosine kinase inhibitor, imatinib (STI571, Gleevec), pointing to the need for development of additional Bcr-Abl tyrosine kinase inhibitors or other therapeutic strategies. It was also found that a significant proportion of patients who received the Bcr-Abl inhibitor did not achieve complete cytogenetic response. Mechanisms for incomplete cytogenetic response to Bcr-Abl inhibition are not entirely clear. We report here three new pyrido[2,3-d]pyrimidine Bcr-Abl tyrosine kinase inhibitors, PD164199, PD173952, PD173958, that induced apoptosis of Bcr-Abl-dependent hematopoietic cells. An interleukin-3 (IL-3) autocrine loop was observed previously in primitive CD34(+)/Bcr-Abl(+) leukemic cells in CML patients. Using 32Dp210(Bcr-Abl)and Baf3p210(Bcr-Abl) cells as models, we tested whether IL-3 might protect Bcr-Abltransformed, IL-3-responsive cells from apoptosis caused by Bcr-Abl tyrosine kinase inhibition. Results of trypan blue exclusion, fluoroisothiocyanate-valyl-alanyl-aspartyl-[O-methyl] -fluoromethylketone (FITC-VAD-FMK), and Annexin-V/7-amino-actinomycin D (7-AAD) binding assays indicate that IL-3 could protect Bcr-Abl-transformed, IL-3 responsive hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. This finding raises the possibility that the IL-3 autocrine loop found in primitive CD34(+)/Bcr-Abl(+) cells in CML patients could contribute to the incomplete eradication of Bcr-Abl(+) cells by Bcr-Abl inhibition.
Dorsey
J F
JF
Molecular Oncology and Experimental Therapeutics Programs, H Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Cunnick
J M
JM
Lanehart
R
R
Huang
M
M
Kraker
A J
AJ
Bhalla
K N
KN
Jove
R
R
Wu
J
J
D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002461:Cell Line, Transformed / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D020014:K562 Cells / Q000187:drug effects; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000517:prevention & control*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014443:Tyrosine / Q000378:metabolism
D017304:Annexin A5; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D014443:Tyrosine; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl