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KIT Signaling Governs Differential Sensitivity of Mature and Primitive CML Progenitors to Tyrosine Kinase Inhibitors
- Source :
- Cancer Research. 73:5775-5786
- Publication Year :
- 2013
- Publisher :
- American Association for Cancer Research (AACR), 2013.
-
Abstract
- Imatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement in CML pathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD34+38− cells. Long-term culture-initiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD34+38+ cells, SCF strongly induced pAKTS473 in a phosphoinositide 3-kinase (PI3K)–dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKTS473 levels remained low in CD34+38− cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34+38− compared with CD34+38+ CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells. Cancer Res; 73(18); 5775–86. ©2013 AACR.
- Subjects :
- Cancer Research
Stromal cell
Cellular differentiation
Blotting, Western
Fusion Proteins, bcr-abl
CD34
Fluorescent Antibody Technique
Antigens, CD34
Apoptosis
Stem cell factor
Biology
Real-Time Polymerase Chain Reaction
Piperazines
Article
Mice
Phosphatidylinositol 3-Kinases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
hemic and lymphatic diseases
Tumor Cells, Cultured
medicine
Animals
Humans
RNA, Messenger
Progenitor cell
Protein Kinase Inhibitors
Cell Proliferation
Phosphoinositide-3 Kinase Inhibitors
Stem Cell Factor
Reverse Transcriptase Polymerase Chain Reaction
Cell Differentiation
Imatinib
Flow Cytometry
medicine.disease
Molecular biology
Proto-Oncogene Proteins c-kit
Pyrimidines
Oncology
Drug Resistance, Neoplasm
Benzamides
Imatinib Mesylate
Neoplastic Stem Cells
Cancer research
Stromal Cells
Tyrosine kinase
medicine.drug
Chronic myelogenous leukemia
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 73
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....2fa9e9362cb565573426ea9b2e79b98a