| Abstract: |
Acute myeloid leukemia (AML) is caused by the cooperation between class I, mostly mutated receptor tyrosine kinases (RTK), and class II oncoproteins, chimeric transcription factors derived from chromosomal translocations. The blasts of 80-90% of AML-patients are positive for the RTK c-Kit. In about 50% of the 'core binding factor' (CBF)-AMLs, c-Kit harbors additional gain-of-function mutations, whereas the t(15;17)-positive AML-M3 (100% c-Kit positive) presents virtually no c-Kit mutations. In all c-Kit-positive AMLs, c-Kit signaling is activated. Here, we investigated the role of c-Kit in the determination of the leukemic phenotype in a model of CBF-AML and AML-M3. We studied the role of aberrant c-Kit signaling on normal and leukemic murine stem cells by RNA interference, the c-Kit-inhibitor Imatinib and a constitutively-activated c-Kit mutant in well-established stem cell assays. Effects of the AML-M3-associated PML/RARα and the AML-1/ ETO as a model for CBF-AML on c-Kit signaling were investigated in trans-activation assays on the Kit promoter. The contribution of activated c-Kit signaling to PML/RARα- and AML-1/ETO-induced leukemogenesis was investigated in a murine transduction/transplantation leukemia model. We report that: i) the inhibition of c-Kit impaired the stem cell capacity of PML/RARα- and AML-1/ETO-positive HSC; ii) PML/RARα was able to activate the c-Kit promoter; iii) constitutively-activated c-Kit increased the stem cell capacity of HSC; and iv) constitutively-activated c-Kit increased the leukemogenic potential of PML/RARα- and AML-1/ETO-positive HSC. Our data provide evidence that c-Kit does not have to be mutated to contribute to the determination of the leukemic phenotype in AML. |
| Keywords: |
signal transduction; controlled study; survival rate; unclassified drug; acute granulocytic leukemia; promoter region; mutation; nonhuman; mutant protein; animal cell; phenotype; animals; mice; cell cycle; imatinib; stem cell factor; proto-oncogene proteins c-kit; gene expression; animal experiment; animal model; rna interference; chromosomes, human, pair 8; cancer model; mice, inbred c57bl; leukemia, promyelocytic, acute; gene activation; blotting, western; hybrid protein; reverse transcriptase polymerase chain reaction; rna, messenger; leukemogenesis; oncogene proteins, fusion; transactivation; hematopoietic stem cells; translocation, genetic; hematopoietic stem cell; core binding factor alpha 2 subunit; chromosomes, human, pair 21; transcription factor runx1; chromosomes, human, pair 17; acute promyelocytic leukemia; aml-1/eto; ckit; class i and ii mutations; pml/rarα; aml1 eto fusion protein; core binding factor; promyelocytic leukemia protein; retinoic acid receptor alpha; retinoic acid receptor alpha promyelocytic leukemia protein fusion protein; oncogene c kit; promyelocyte; chromosomes, human, pair 15
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