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MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance.
van der Zwet, Jordy C G; Buijs-Gladdines, Jessica G C A M; Cordo', Valentina; Debets, Donna O; Smits, Willem K; Chen, Zhongli; Dylus, Jelle; Zaman, Guido J R; Altelaar, Maarten; Oshima, Koichi; Bornhauser, Beat; Bourquin, Jean-Pierre; Cools, Jan; Ferrando, Adolfo A; Vormoor, Josef; Pieters, Rob; Vormoor, Britta; Meijerink, Jules P P.
Afiliação
  • van der Zwet JCG; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Buijs-Gladdines JGCAM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Cordo' V; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Debets DO; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center of Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
  • Smits WK; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Chen Z; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Dylus J; Netherlands Translational Research Center B.V., Oss, the Netherlands.
  • Zaman GJR; Netherlands Translational Research Center B.V., Oss, the Netherlands.
  • Altelaar M; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center of Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
  • Oshima K; Institute of Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
  • Bornhauser B; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
  • Bourquin JP; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
  • Cools J; KU Leuven Center for Human Genetics & VIB Center for Cancer Biology, Leuven, Belgium.
  • Ferrando AA; Institute of Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
  • Vormoor J; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Pieters R; Newcastle University, Newcastle upon Tyne, UK.
  • Vormoor B; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Meijerink JPP; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Leukemia ; 35(12): 3394-3405, 2021 12.
Article em En | MEDLINE | ID: mdl-34007050
(Patho-)physiological activation of the IL7-receptor (IL7R) signaling contributes to steroid resistance in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Here, we show that activating IL7R pathway mutations and physiological IL7R signaling activate MAPK-ERK signaling, which provokes steroid resistance by phosphorylation of BIM. By mass spectrometry, we demonstrate that phosphorylated BIM is impaired in binding to BCL2, BCLXL and MCL1, shifting the apoptotic balance toward survival. Treatment with MEK inhibitors abolishes this inactivating phosphorylation of BIM and restores its interaction with anti-apoptotic BCL2-protein family members. Importantly, the MEK inhibitor selumetinib synergizes with steroids in both IL7-dependent and IL7-independent steroid resistant pediatric T-ALL PDX samples. Despite the anti-MAPK-ERK activity of ruxolitinib in IL7-induced signaling and JAK1 mutant cells, ruxolitinib only synergizes with steroid treatment in IL7-dependent steroid resistant PDX samples but not in IL7-independent steroid resistant PDX samples. Our study highlights the central role for MAPK-ERK signaling in steroid resistance in T-ALL patients, and demonstrates the broader application of MEK inhibitors over ruxolitinib to resensitize steroid-resistant T-ALL cells. These findings strongly support the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507) and contributes to the optimization and stratification of newly designed T-ALL treatment regimens.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esteroides / Resistencia a Medicamentos Antineoplásicos / Proteínas Quinases Ativadas por Mitógeno / MAP Quinases Reguladas por Sinal Extracelular / Inibidores de Proteínas Quinases / Leucemia-Linfoma Linfoblástico de Células T Precursoras Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Leukemia Assunto da revista: HEMATOLOGIA / NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esteroides / Resistencia a Medicamentos Antineoplásicos / Proteínas Quinases Ativadas por Mitógeno / MAP Quinases Reguladas por Sinal Extracelular / Inibidores de Proteínas Quinases / Leucemia-Linfoma Linfoblástico de Células T Precursoras Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Leukemia Assunto da revista: HEMATOLOGIA / NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Holanda