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Therapeutic targeting of Src-kinase Lyn in myeloid leukemic cell growth
V Roginskaya1, S Zuo, E Caudell
1Department of Pediatrics, Children's Hospital of Pittsburgh, PA 15213, USA.
Abstract:
Protein tyrosine kinases play a major role in promoting cell growth, and their activity in solid tumors is well established. Inhibitors of protein tyrosine kinases are now in advanced clinical trials for the treatment of breast and brain cancers. Because Src-related PTK have been shown to be activated in leukemic cell lines, we studied their activation in human myeloid leukemia. Blasts from the majority of patients with acute leukemia showed constitutive activity of the Src kinase Lyn. In contrast, no patient samples showed constitutive activation of Jak2. Genetic and pharmacologic targeting of Lyn was used to determine its contribution to leukemic cell growth. Antisense Lyn oligonucleotide treatment resulted in the inhibition of tritiated thymidine incorporation following GM-CSF stimulation of the factor-dependent line MO7e. The Src kinase inhibitor PD166285 inhibited the growth of human leukemic cell lines and leukemic blasts. When combined with doxorubicin, an additive effect on the inhibition of leukemic cell growth occurred. These studies demonstrate the importance of Src kinases in promoting leukemic cell growth and suggests that further development of agents which target Src kinases and their inclusion in multidrug regimens are warranted for novel therapies of myeloid leukemia.
Insights
Src kinase Lyn is activated in most acute myeloid leukemia patients, driving cancer cell growth. Targeting Lyn with inhibitors or antisense oligonucleotides shows promise for new leukemia therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Protein tyrosine kinases (PTKs) are crucial for cell growth and are implicated in solid tumors.
- Src-related PTKs are activated in leukemia cell lines, suggesting a role in myeloid leukemia.
Purpose of the Study:
- To investigate the activation of Src-related PTKs, specifically Lyn and Jak2, in human myeloid leukemia.
- To determine the contribution of Lyn kinase to leukemic cell proliferation and evaluate potential therapeutic strategies targeting Lyn.
Main Methods:
- Analysis of Src kinase activation in patient samples of acute myeloid leukemia.
- Treatment of factor-dependent leukemic cell line MO7e with antisense Lyn oligonucleotides.
- Inhibition of human leukemic cell lines and blasts using the Src kinase inhibitor PD166285, alone and in combination with doxorubicin.
Main Results:
- Constitutive activation of the Src kinase Lyn was observed in blasts from the majority of acute leukemia patients.
- No constitutive activation of Jak2 was found in patient samples.
- Antisense Lyn oligonucleotide treatment inhibited thymidine incorporation in MO7e cells stimulated with GM-CSF.
- The Src kinase inhibitor PD166285 effectively inhibited the growth of human leukemic cell lines and blasts.
- Combining PD166285 with doxorubicin resulted in an additive inhibitory effect on leukemic cell growth.
Conclusions:
- Src kinases, particularly Lyn, play a significant role in promoting the growth of myeloid leukemia cells.
- Targeting Src kinases with specific inhibitors or antisense oligonucleotides represents a promising therapeutic avenue for myeloid leukemia.
- Further development of Src kinase inhibitors and their incorporation into multidrug regimens may lead to novel therapies for myeloid leukemia.