UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia

Aissa Benyoucef, Carmen G. Palii, Chaochen Wang, Christopher J. Porter, Alphonse Chu, Fengtao Dai, Véronique Tremblay, Patricia Rakopoulos, Kulwant Singh, Suming Huang, Francoise Pflumio, Josée Hébert, Jean Francois Couture, Theodore J. Perkins, Kai Ge, F. Jeffrey Dilworth, Marjorie Brand

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtypespecific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.

Original languageEnglish (US)
Pages (from-to)508-521
Number of pages14
JournalGenes and Development
Volume30
Issue number5
DOIs
StatePublished - Mar 1 2016

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All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Cite this

Benyoucef, A., Palii, C. G., Wang, C., Porter, C. J., Chu, A., Dai, F., Tremblay, V., Rakopoulos, P., Singh, K., Huang, S., Pflumio, F., Hébert, J., Couture, J. F., Perkins, T. J., Ge, K., Dilworth, F. J., & Brand, M. (2016). UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes and Development, 30(5), 508-521. https://doi.org/10.1101/gad.276790.115