BCR-ABL Kinase Activity-Independent Signaling Pathway in Chronic Myelogenous Leukemia

摘要

The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) is the preferred treatment for human chronic myeloid leukemia (CML), but does not cure mice with BCR-ABL-induced acute lymphoblastic leukemia (ALL), similar to CML lymphoid blast crisis. The inability of imatinib to cure CML in mice leads us to hypothesize that a BCR-ABL kinase activity-independent pathway also plays a critical role in the development of this disease. We identified Src kinases as key molecules in this BCR-ABL kinase activity-independent pathway, and they are 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 affords complete B-ALL remission. However, leukemic stem cell pathways must be targeted for curative therapy of Ph+ leukemia. We have identified CML stem cells in mice, and found that these cells are insensitive to imatinib therapy. Our study suggests that Src kinases may be effective in inhibiting leukemic stem cells, and combination therapy using a BCR-ABL/Src inhibitor and an anti-stem cells agent would be beneficial to CML patients. Our work will provide a new therapeutic strategy for CML.