Related Experiment Video
Updated: Jul 19, 2026
Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+
Yiguo Hu1, Sarah Swerdlow, Theodore M Duffy
1The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Abstract:
It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and cure of the disease. Imatinib is highly effective at treating human Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but not Ph(+) B cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells, suggesting that imatinib does not inactivate all BCR-ABL-activated signaling pathways. This SRC pathway is essential for leukemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Inhibition of both SRC and BCR-ABL kinase activities by dasatinib affords complete B-ALL remission. However, curing B-ALL and CML mice requires killing leukemic stem cells insensitive to both imatinib and dasatinib. Besides BCR-ABL and SRC kinases, stem cell pathways must be targeted for curative therapy of Ph(+) leukemia.
Insights
Imatinib does not fully inactivate BCR-ABL signaling in leukemia, allowing SRC kinases to drive resistance. Targeting SRC and leukemic stem cells is crucial for a cure in Philadelphia chromosome-positive leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Imatinib effectively treats chronic phase Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML).
- However, imatinib is less effective against Ph(+) B cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis.
- BCR-ABL kinase activity is a key driver in these leukemias.
Purpose of the Study:
- To investigate why imatinib fails to completely inhibit BCR-ABL signaling in certain leukemias.
- To identify alternative pathways contributing to imatinib resistance.
- To explore curative therapeutic strategies for Ph(+) leukemias.
Main Methods:
- Utilized mouse models of Ph(+) leukemia.
- Analyzed kinase activity in imatinib-treated leukemic cells.
- Assessed the efficacy of combined kinase inhibition and stem cell targeting.
Main Results:
- SRC kinases remain active in imatinib-treated leukemic cells, indicating incomplete pathway inactivation.
- The active SRC pathway is essential for leukemic cell survival and disease progression to blast crisis.
- Dasatinib, inhibiting both BCR-ABL and SRC, achieved complete B-ALL remission.
- Leukemic stem cells resistant to both imatinib and dasatinib were identified.
Conclusions:
- Imatinib does not fully suppress BCR-ABL-driven signaling due to persistent SRC kinase activity.
- Targeting both BCR-ABL and SRC kinases is necessary for initial remission.
- Curative therapy for Ph(+) leukemia requires eliminating drug-resistant leukemic stem cells by targeting additional stem cell pathways.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...