The protein tyrosine kinase inhibitor SU5614 inhibits VEGF-induced endothelial cell sprouting and induces growth arrest and apoptosis by inhibition of c-kit in AML cells

Spiekermann, Karsten; Faber, Florian; Voswinckel, Robert; Hiddemann, Wolfgang

doi:10.1016/s0301-472x(02)00837-8

Cited by 58 publications

(48 citation statements)

References 27 publications

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“…During the preparation of this manuscript, Heissig et al also noted an absence of EPC mobilization in the Sl/Sl d mouse, which bears mutations in the c-kit ligand (SCF) in response to hind-limb ischemia, further supporting the observations in the present report (43). Furthermore, Gleevec is also known to suppresses VEGF secretion and limit sprouting angiogenesis (44,45), consistent with our series of observations.…”

Section: Discussionsupporting

confidence: 89%

Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines

Fazel

Cimini²,

Chen³

et al. 2006

Journal of Clinical Investigation

483

368

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Clinical trials of bone marrow stem/progenitor cell therapy after myocardial infarction (MI) have shown promising results, but the mechanism of benefit is unclear. We examined the nature of endogenous myocardial repair that is dependent on the function of the c-kit receptor, which is expressed on bone marrow stem/ progenitor cells and on recently identified cardiac stem cells. MI increased the number of c-kit + cells in the heart. These cells were traced back to a bone marrow origin, using genetic tagging in bone marrow chimeric mice. The recruited c-kit + cells established a proangiogenic milieu in the infarct border zone by increasing VEGF and by reversing the cardiac ratio of angiopoietin-1 to angiopoietin-2. These oscillations potentiated endothelial mitogenesis and were associated with the establishment of an extensive myofibroblast-rich repair tissue. Mutations in the c-kit receptor interfered with the mobilization of the cells to the heart, prevented angiogenesis, diminished myofibroblast-rich repair tissue formation, and led to precipitous cardiac failure and death. Replacement of the mutant bone marrow with wild-type cells rescued the cardiomyopathic phenotype. We conclude that, consistent with their documented role in tumorigenesis, bone marrow c-kit + cells act as key regulators of the angiogenic switch in infarcted myocardium, thereby driving efficient cardiac repair.

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Section: Discussionsupporting

confidence: 89%

Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines

Fazel

Cimini²,

Chen³

et al. 2006

Journal of Clinical Investigation

483

368

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“…To optimize transduction efficiency, the virus-containing medium (VCM) of different constructs was used to transfect GP + E86 cells to establish stable packaging cell lines, or to directly infect 5-FU-mobilized BM cells in the case of FLT3-LM. Ba/F3 cells were transfected with the different constructs as previously described (48,49).…”

Section: Figurementioning

confidence: 99%

The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice

Schessl¹,

Rawat²,

Cusan³

et al. 2005

J. Clin. Invest.

Self Cite

209

179

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The molecular characterization of leukemia has demonstrated that genetic alterations in the leukemic clone frequently fall into 2 classes, those affecting transcription factors (e.g., AML1-ETO) and mutations affecting genes involved in signal transduction (e.g., activating mutations of FLT3 and KIT). This finding has favored a model of leukemogenesis in which the collaboration of these 2 classes of genetic alterations is necessary for the malignant transformation of hematopoietic progenitor cells. The model is supported by experimental data indicating that AML1-ETO and FLT3 length mutation (FLT3-LM), 2 of the most frequent genetic alterations in AML, are both insufficient on their own to cause leukemia in animal models. Here we report that AML1-ETO collaborates with FLT3-LM in inducing acute leukemia in a murine BM transplantation model. Moreover, in a series of 135 patients with AML1-ETO-positive AML, the most frequently identified class of additional mutations affected genes involved in signal transduction pathways including FLT3-LM or mutations of KIT and NRAS. These data support the concept of oncogenic cooperation between AML1-ETO and a class of activating mutations, recurrently found in patients with t(8;21), and provide a rationale for therapies targeting signal transduction pathways in AML1-ETO-positive leukemias. IntroductionThe cloning of recurring chromosomal translocations and, increasingly, the molecular characterization of point mutations in patients with acute leukemia have substantially contributed to the understanding of the pathogenesis of this disease. In acute myeloid leukemia (AML), chromosomal translocations most frequently target transcription factors involved in the regulation of normal hematopoietic differentiation, whereas point mutations often affect genes involved in signal transduction pathways associated with cell proliferation (1-3). The systematic analyses of genetic alterations in patients with AML have demonstrated that genetic lesions of more than 1 transcriptional regulator, such as AML1-ETO (RUNX1-MTG8), HOX fusion genes, or PML-RARA, rarely occur in the leukemic clone. Similarly, patients with concurrent mutations of FLT3, KIT, or NRAS are rare. However, there are numerous examples in which fusion genes are identified together with activating mutations of receptor tyrosine kinases, exemplified by PML-RARA and the FLT3 length mutation (FLT3-LM), which occur together in up to 35% of all patients with t(15;17)-positive AML (4).

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“…38,39 Morevover, c-kit has been found to be phosphorylated in the absence of SCF in most cases of AML and inhibition of its tyrosine kinase activity by SU5416 and SU6668 induces apoptosis in AML cells. [40][41][42] Interestingly, c-kit is mutated in a large percentage of AML cases bearing either t(8;21)(q22;q22) or inv(16)(p13;q22) chromosomal abnormalities, also defined as core binding factorleukemias. [43][44][45] Wang and coll.…”

Section: Hypothetical Up-stream Regulators Of Mtor In Amlmentioning

confidence: 99%

mTOR, A New Therapeutic Target in Acute Myeloid Leukemia

Récher¹,

Santos²,

Demur³

et al. 2005

Cell Cycle

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The protein tyrosine kinase inhibitor SU5614 inhibits VEGF-induced endothelial cell sprouting and induces growth arrest and apoptosis by inhibition of c-kit in AML cells

Cited by 58 publications

References 27 publications

Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines

Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines

The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice

mTOR, A New Therapeutic Target in Acute Myeloid Leukemia

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