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)

Apart from endothelial cells, the receptor tyrosine kinase TEK/Tie-2 is also expressed by primitive hematopoietic stem cells. While the role of this receptor and its ligand angiopoietin-1 (ang-1) during angiogenesis has been intensively studied before, little is known about their function in normal or malignant hematopoiesis. Recently several studies suggested that TEK plays an important role in the proliferation of primitive hematopoietic cells. We, therefore, analyzed blood cells of healthy donors and leukemia patients for expression of TEK and ang-1 by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Northern blotting. We found an increased expression of the receptor and its ligand in 11 of 17 cases of acute and chronic myeloid leukemia (CML) but not in four lymphocytic leukemias or five myeloid leukemias in remission. Abundant ang-1 message could also be detected in 4/6 myeloid and 1/9 cell lines of lymphocytic origin, but only one cell line co-expressed the TEK receptor, suggesting that ang-1 and TEK were probably expressed by different subsets of cells in the leukemic samples. Recently, several studies have indicated that angiogenic factors like ang-1 and vascular endothelial growth factor can enhance the proliferation of normal and malignant hematopoietic cells. The expression of both the TEK receptor and its ligand in acute myeloid leukemia (AML) and CML patients might, therefore, suggest an involvement of these genes in the pathogenesis of myeloproliferative disorders.
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PMID:Expression of angiopoietin-1 and its receptor TEK in hematopoietic cells from patients with myeloid leukemia. 1175 66

The BCR/ABL1 inhibitor Nilotinib is increasingly used to treat patients with chronic myeloid leukemia (CML). Although otherwise well-tolerated, Nilotinib has been associated with the occurrence of progressive arterial occlusive disease (AOD). Our objective was to determine the exact frequency of AOD and examine in vitro and in vivo effects of Nilotinib and Imatinib on endothelial cells to explain AOD-development. In contrast to Imatinib, Nilotinib was found to upregulate pro-atherogenic adhesion-proteins (ICAM-1, E-selectin, VCAM-1) on human endothelial cells. Nilotinib also suppressed endothelial cell proliferation, migration and tube-formation and bound to a distinct set of target-kinases, relevant to angiogenesis and atherosclerosis, including angiopoietin receptor-1 TEK, ABL-2, JAK1 and MAP-kinases. Nilotinib and siRNA against ABL-2 also suppressed KDR expression. In addition, Nilotinib augmented atherosclerosis in ApoE-/- mice and blocked reperfusion and angiogenesis in a hindlimb-ischemia model of arterial occlusion, whereas Imatinib showed no comparable effects. Clinically overt AOD-events were found to accumulate over time in Nilotinib-treated patients. After a median observation-time of 2.0 years, the AOD-frequency was higher in these patients (29.4%) compared to risk factor- and age-matched controls (<5%). Together, Nilotinib exerts direct pro-atherogenic and anti-angiogenic effects on vascular endothelial cells, which may contribute to development of AOD in patients with CML.
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PMID:Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site. 2875 17