Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Bcr-Abl tyrosine kinase activates various signaling pathways including nuclear factor kappaB that mediate proliferation, transformation, and apoptosis resistance in Bcr-Abl(+) myeloid leukemia cells. Here we report that protein kinase (PK) D2, a serine threonine kinase of the PKD family, is a novel substrate of Bcr-Abl. PKD2 was found to be the major isoform of the PKD family expressed in chronic myeloid leukemia cells and is tyrosine phosphorylated by Bcr-Abl in its pleckstrin homology domain. A mutant that mimicks tyrosine phosphorylation of PKD2 in the pleckstrin homology domain activates nuclear factor kappaB independently of its catalytic activity. Furthermore, our data show that Bcr-Abl-induced activation of the nuclear factor kappaB cascade in LAMA84 cells is largely mediated by tyrosine-phosphorylated PKD2. These data present a novel mechanism of Bcr-Abl-induced nuclear factor kappaB activation in myeloid leukemia. Targeting PKD2 tyrosine phosphorylation, not its kinase activity, could be a novel therapeutic approach for the treatment of Bcr-Abl(+) myeloid leukemia.
 ...
PMID:Protein kinase D2 mediates activation of nuclear factor kappaB by Bcr-Abl in Bcr-Abl+ human myeloid leukemia cells. 1560 56

Nilotinib, a second-generation tyrosine kinase inhibitor with 20- to 30-fold greater potency than imatinib, was developed to overcome imatinib intolerance or resistance. Recently, nilotinib has been approved as a first-line treatment for chronic myelogenous leukemia in the US and Japan. Tumor lysis syndrome (TLS) is an extremely rare adverse event that can occur during treatment with nilotinib, with only a few reported cases to date. Herein, we report two patients who developed TLS soon after the start of treatment with nilotinib. While in the first case, which co-presented with underlying mild-to-moderate renal insufficiency due to polycystic kidney disease, the TLS resolved on discontinuation of the drug, the second patient, who had an exceedingly high white blood cell count, presented with disseminated intravascular coagulation and severe liver injury triggered by TLS that developed after the start of nilotinib treatment, and died of multiple organ failure. Therefore, caution is necessary when this drug is used in the first-line setting in patients with renal insufficiency or a high tumor burden.
...
PMID:Tumor lysis syndrome soon after treatment with hydroxyurea followed by nilotinib in two patients with chronic-phase chronic myelogenous leukemia. 2364 69