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Exploring the oncogenic and therapeutic target potential of the MYB-TYK2 fusion gene in B-cell acute lymphoblastic leukemia.
Shirazi, Paniz Tavakoli; Eadie, Laura N; Heatley, Susan L; Page, Elyse C; François, Maxime; Hughes, Timothy P; Yeung, David; White, Deborah L.
Afiliación
  • Shirazi PT; Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
  • Eadie LN; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
  • Heatley SL; Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
  • Page EC; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
  • François M; Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
  • Hughes TP; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
  • Yeung D; Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
  • White DL; Faculty of Sciences, University of Adelaide, Adelaide, SA, Australia.
Cancer Gene Ther ; 29(8-9): 1140-1152, 2022 08.
Article en En | MEDLINE | ID: mdl-35022522
TYK2-rearrangements have recently been identified in high-risk acute lymphoblastic leukemia (HR-ALL) cases and are associated with poor outcome. Current understanding of the leukemogenic potential and therapeutic targetability of activating TYK2 alterations in the ALL setting is unclear, thus further investigations are warranted. Consequently, we developed in vitro, and for the first time, in vivo models of B-cell ALL from a patient harboring the MYB-TYK2 fusion gene. These models revealed JAK/STAT signaling activation and the oncogenic potential of the MYB-TYK2 fusion gene in isolation. High throughput screening identified the HDAC inhibitor, vorinostat and the HSP90 inhibitor, tanespimycin plus the JAK inhibitor, cerdulatinib as the most effective agents against cells expressing the MYB-TYK2 alteration. Evaluation of vorinostat and cerdulatinib in pre-clinical models of MYB-TYK2-rearranged ALL demonstrated that both drugs exhibited anti-leukemic effects and reduced the disease burden in treated mice. Importantly, these findings indicate that activating TYK2 alterations can function as driver oncogenes rather than passenger or secondary events in disease development. In addition, our data provide evidence for use of vorinostat and cerdulatinib in the treatment regimens of patients with this rare yet aggressive type of high-risk ALL that warrants further investigation in the clinical setting.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia-Linfoma Linfoblástico de Células Precursoras / Inhibidores de las Cinasas Janus Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cancer Gene Ther Asunto de la revista: GENETICA MEDICA / NEOPLASIAS / TERAPEUTICA Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia-Linfoma Linfoblástico de Células Precursoras / Inhibidores de las Cinasas Janus Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cancer Gene Ther Asunto de la revista: GENETICA MEDICA / NEOPLASIAS / TERAPEUTICA Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido