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1.
Blood ; 119(18): 4253-63, 2012 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-22411871

RESUMEN

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.


Asunto(s)
Complejo III de Transporte de Electrones/metabolismo , Inestabilidad Genómica , Leucemia Mieloide de Fase Crónica/patología , Proteínas de Neoplasias/fisiología , Células Madre Neoplásicas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Unión al GTP rac/fisiología , Animales , Catalasa/metabolismo , Daño del ADN , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Progresión de la Enfermedad , Transporte de Electrón , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Potencial de la Membrana Mitocondrial , Metacrilatos/farmacología , Ratones , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Policitemia Vera/metabolismo , Policitemia Vera/patología , Proteínas Recombinantes de Fusión/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/fisiología , Superóxido Dismutasa/metabolismo , Tiazoles/farmacología , Proteínas de Unión al GTP rac/antagonistas & inhibidores , Proteínas de Unión al GTP rac/genética , Proteína RCA2 de Unión a GTP
2.
Mol Cell Biol ; 25(18): 8001-8, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16135792

RESUMEN

The p85alpha subunit of phosphatidylinositol 3-kinase (PI-3k) forms a complex with a protein network associated with oncogenic fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGFbetaR, and NPM/ALK, resulting in constitutive activation of the p110 catalytic subunit of PI-3k. Introduction of point mutations in the N-terminal and C-terminal SH2 domain and SH3 domain of p85alpha, which disrupt their ability to bind phosphotyrosine and proline-rich motifs, respectively, abrogated their interaction with the BCR/ABL protein network. The p85alpha mutant protein (p85mut) bearing these mutations was unable to interact with BCR/ABL and other FTKs, while its binding to the p110alpha catalytic subunit of PI-3k was intact. In addition, binding of Shc, c-Cbl, and Gab2, but not Crk-L, to p85mut was abrogated. p85mut diminished BCR/ABL-dependent activation of PI-3k and Akt kinase, the downstream effector of PI-3k. This effect was associated with the inhibition of BCR/ABL-dependent growth of the hematopoietic cell line and murine bone marrow cells. Interestingly, the addition of interleukin-3 (IL-3) rescued BCR/ABL-transformed cells from the inhibitory effect of p85mut. SCID mice injected with BCR/ABL-positive hematopoietic cells expressing p85mut survived longer than the animals inoculated with BCR/ABL-transformed counterparts. In conclusion, we have identified the domains of p85alpha responsible for the interaction with the FTK protein network and transduction of leukemogenic signaling.


Asunto(s)
Proteínas de Fusión bcr-abl/metabolismo , Leucemia/metabolismo , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Bovinos , Línea Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Humanos , Leucemia/genética , Ratones , Ratones SCID , Mutación , Fosfatidilinositol 3-Quinasas/genética , Fosfotirosina/metabolismo , Mapeo de Interacción de Proteínas , Dominios Homologos src
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