Imatinib mesylate, an inhibitor of the BcrAbl tyrosine kinase, has modest activity in refractory/relapsed Philadelphia chromosome (Ph)–positive acute lymphocytic leukemia (ALL). Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. There were 20 patients who received hyper–CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and ima...

More than 95% of patients with chronic myelogenous leukemia (CML) contain an abnormal chromosome termed the Philadelphia chromosome (Ph1). I'll1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. The product of the fused BCR-ABL genes is a protein of about 2000 amino acids termed P210 BCR-ABL. Although the BCRABL protein can be routinely detected in blood cells from bl...

The BCR-ABL oncogene is responsible for most cases of chronic myelogenous leukemia and some acute lymphoblastic leukemias. The fusion protein encoded by BCR-ABL possesses an aberrantly regulated tyrosine kinase activity. Imatinib mesylate (Gleevec, STI-571) is an inhibitor of ABL tyrosine kinase activity that has been remarkably effective in slowing disease progression in patients with chronic ...

Previous studies suggested that the SH2-containing inositol-5-phosphatase (SHIP) may play a tumor suppressor-like function in BCR-ABL-mediated leukemogenesis. To investigate this possibility, we first developed a new assay for quantitating transplantable multilineage leukemia-initiating cells (L-ICs) in hematopoietic stem cell (HSC)-enriched mouse bone marrow (BM) cells transduced with a BCR-AB...

In this project, we systematically use several computational techniques such as charge optimization and component analysis to study molecular recognition and binding in the chronic myeloid leukemia (CML) drug systems. Using CML drugs and their biological target, the BcrAbl oncoprotein, we systematically conduct a comparative analysis on five CML drugs bound to both the wild-type (WT) and T315I ...

In chronic myeloid leukemia (CML), mechanisms of resistance to imatinib mesylate (Glivec), a selective Bcr-Abl kinase inhibitor, have been traced to Bcr-Abl reactivation, most frequently by mutations in the kinase domain of Bcr-Abl, or to BCRABL amplification. Bcr-Abl overexpression not only directly modulates sensitivity to imatinib, it may also indirectly influence treatment response by influ...

The tyrosine kinase inhibitor STI571 is a promising agent for the treatment of advanced Philadelphia chromosome positive (Ph1) acute lymphoblastic leukemia (ALL), but resistance develops rapidly in most patients after an initial response. To identify mechanisms of resistance to STI571, 30 complementary DNAs (including 9 matched samples) obtained from the bone marrow of individuals with Ph1 ALL ...

Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collective...

The biological target for interferon (IFN)a in chronic myeloid leukemia (CML) is unknown, but one possibility is that amplification of granulocyte-macrophage colony-forming cells (CFU-GM) is reduced. Replating CFU-GM colonies and observing secondary colony formation provides a measure of CFU-GM amplification. Amplification of CML, but not normal, CFU-GM in vitro was significantly inhibited by I...

The development of targeted therapies has revolutionized the treatment of cancer patients. The identification of "druggable" oncogenic kinases and the creation of small-molecule inhibitors designed to specifically target these mutant kinases have become an important therapeutic paradigm across several different malignancies. Often these inhibitors induce dramatic clinical responses in molecular...