Cooperation between constitutively activated c-kit signaling and leukemogenic transcription factors in the determination of the leukemic phenotype in murine hematopoietic stem cells.

Zheng, Xiaomin, Oancea, Claudia, Henschler, Reinhard and Ruthardt, Martin ORCID: https://orcid.org/0000-0003-1021-3811 2009. Cooperation between constitutively activated c-kit signaling and leukemogenic transcription factors in the determination of the leukemic phenotype in murine hematopoietic stem cells. International Journal of Oncology 34 (6) , pp. 1521-1531. 10.3892/ijo_00000281

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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/RARalpha 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/RARalpha- 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/RARalpha- and AML-1/ETO-positive HSC; ii) PML/RARalpha 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/RARalpha- 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Spandidos Publications
ISSN:	1019-6439
Last Modified:	22 Feb 2024 15:45
URI:	https://orca.cardiff.ac.uk/id/eprint/166076

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