BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia - Université Clermont Auvergne Accéder directement au contenu
Article Dans Une Revue Blood Année : 2021

BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia

Charles Herbaux
Christoph Kornauth
  • Fonction : Auteur
Stéphanie Poulain
  • Fonction : Auteur
Stephen Chong
  • Fonction : Auteur
Mary Collins
  • Fonction : Auteur
Rebecca Valentin
Liam Hackett
  • Fonction : Auteur
François Lemonnier
Jehan Dupuis
  • Fonction : Auteur
Adrien Daniel
  • Fonction : Auteur
Cecile Tomowiak
  • Fonction : Auteur
Kamel Laribi
Loïc Renaud
Damien Roos-Weil
Cedric Rossi
Eric van den Neste
  • Fonction : Auteur
Cecile Leyronnas
  • Fonction : Auteur
Fatiha Merabet
  • Fonction : Auteur
Jean Valère Malfuson
  • Fonction : Auteur
Mourad Tiab
  • Fonction : Auteur
Loïc Ysebaert
Samuel Ng
  • Fonction : Auteur
Franck Morschhauser
Philipp Staber
  • Fonction : Auteur
Matthew Davids

Résumé

Abstract Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine–based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.

Domaines

Hématologie

Dates et versions

hal-03440992 , version 1 (22-11-2021)

Identifiants

Citer

Charles Herbaux, Christoph Kornauth, Stéphanie Poulain, Stephen Chong, Mary Collins, et al.. BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia. Blood, 2021, 137 (25), pp.3495-3506. ⟨10.1182/blood.2020007303⟩. ⟨hal-03440992⟩
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