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2.
Nat Cancer ; 2(12): 1372-1386, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-35121903

RESUMEN

Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rGBM, including patients that do not harbor BRAF/PTPN11 mutations. Here we show that immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, is predictive of overall survival following adjuvant PD-1 blockade in two independent rGBM patient cohorts. Single-cell RNA-sequencing and multiplex immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and that high-p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. These findings indicate that ERK1/2 activation in rGBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.


Asunto(s)
Glioblastoma , Glioblastoma/tratamiento farmacológico , Humanos , Inmunoterapia , Sistema de Señalización de MAP Quinasas , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fosforilación
3.
Genes Dev ; 33(1-2): 61-74, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30573454

RESUMEN

Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.


Asunto(s)
Endopeptidasas/metabolismo , Leucemia/terapia , Proteína de la Leucemia Mieloide-Linfoide/genética , Animales , Cromatina/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Endopeptidasas/genética , Inhibidores Enzimáticos/farmacología , Técnicas de Inactivación de Genes , Células HCT116 , Células HEK293 , Humanos , Leucemia/enzimología , Leucemia/genética , Células MCF-7 , Ratones , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Estabilidad Proteica , Análisis de Supervivencia
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