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

  • Authors:
    • Xiaomin Zheng
    • Claudia Oancea
    • Reinhard Henschler
    • Martin Ruthardt
  • View Affiliations

  • Published online on: June 1, 2009     https://doi.org/10.3892/ijo_00000281
  • Pages: 1521-1531
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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/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.

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June 2009
Volume 34 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Zheng X, Oancea C, Henschler R and Ruthardt M: Cooperation between constitutively activated c-Kit signaling and leukemogenic transcription factors in the determination of the leukemic phenotype in murine hematopoietic stem cells. Int J Oncol 34: 1521-1531, 2009.
APA
Zheng, X., Oancea, C., Henschler, R., & Ruthardt, M. (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, 1521-1531. https://doi.org/10.3892/ijo_00000281
MLA
Zheng, X., Oancea, C., Henschler, R., Ruthardt, M."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 (2009): 1521-1531.
Chicago
Zheng, X., Oancea, C., Henschler, R., Ruthardt, M."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, no. 6 (2009): 1521-1531. https://doi.org/10.3892/ijo_00000281