Acute sensitivity of Ph-like acute lymphoblastic leukemia to the SMAC-mimetic birinapant

Jennifer Richmond, Alissa Robbins, Kathryn Evans, Dominik Beck, Raushan T. Kurmasheva, Catherine A. Billups, Hernan Carol, Sue Heatley, Rosemary Sutton, Glenn M. Marshall, Deborah White, John Pimanda, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock

Resultado de la investigación: Articlerevisión exhaustiva

15 Citas (Scopus)

Resumen

Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment.

Idioma originalEnglish (US)
Páginas (desde-hasta)4579-4591
Número de páginas13
PublicaciónCancer Research
Volumen76
N.º15
DOI
EstadoPublished - ago. 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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