Mimicry of a constitutively active pre-B cell receptor in acute lymphoblastic leukemia cells.
J Exp Med
; 201(11): 1837-52, 2005 Jun 06.
Article
en En
| MEDLINE
| ID: mdl-15939795
ABSTRACT
Pre-B cells undergo apoptosis unless they are rescued by pre-B cell receptor-dependent survival signals. We previously showed that the BCR-ABL1 kinase that is expressed in pre-B lymphoblastic leukemia bypasses selection for pre-B cell receptor-dependent survival signals. Investigating possible interference of BCR-ABL1 with pre-B cell receptor signaling, we found that neither SYK nor SLP65 can be phosphorylated in response to pre-B cell receptor engagement. Instead, Bruton's tyrosine kinase (BTK) is constitutively phosphorylated by BCR-ABL1. Activated BTK is essential for survival signals that otherwise would arise from the pre-B cell receptor, including activation of PLCgamma1, autonomous Ca2+ signaling, STAT5-phosphorylation, and up-regulation of BCLX(L). Inhibition of BTK activity specifically induces apoptosis in BCR-ABL1+ leukemia cells to a similar extent as inhibition of BCR-ABL1 kinase activity itself. However, BCR-ABL1 cannot directly bind to full-length BTK. Instead, BCR-ABL1 induces the expression of a truncated splice variant of BTK that acts as a linker between the two kinases. As opposed to full-length BTK, truncated BTK lacks kinase activity yet can bind to BCR-ABL1 through its SRC-homology domain 3. Acting as a linker, truncated BTK enables BCR-ABL1-dependent activation of full-length BTK, which initiates downstream survival signals and mimics a constitutively active pre-B cell receptor.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Glicoproteínas de Membrana
/
Regulación Leucémica de la Expresión Génica
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Imitación Molecular
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Señalización del Calcio
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Leucemia-Linfoma Linfoblástico de Células Precursoras
Límite:
Adolescent
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Adult
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Aged
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Child
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Child, preschool
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Exp Med
Año:
2005
Tipo del documento:
Article
País de afiliación:
Alemania