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Selective inhibition of HDAC class IIA as therapeutic intervention for KMT2A-rearranged acute lymphoblastic leukemia.

Authors :
Verbeek TCAI
Vrenken KS
Arentsen-Peters STCJM
Castro PG
van de Ven M
van Tellingen O
Pieters R
Stam RW
Source :
Communications biology [Commun Biol] 2024 Oct 04; Vol. 7 (1), pp. 1257. Date of Electronic Publication: 2024 Oct 04.
Publication Year :
2024

Abstract

KMT2A-rearranged acute lymphoblastic leukemia (ALL) is characterized by deregulation of the epigenome and shows susceptibility towards histone deacetylase (HDAC) inhibition. Most broad-spectrum HDAC inhibitors simultaneously target multiple human HDAC isoforms. Consequently, they often induce toxicity and especially in combination with other therapeutic agents. Therefore, more specifically targeting HDAC isoforms may represent a safer therapeutic strategy. Here we show that shRNA-mediated knock-down of the class IIA HDAC isoforms HDAC4, HDAC5, and HDAC7 results in apoptosis induction and cell cycle arrest in KMT2A-rearranged ALL cells. In concordance, the HDAC4/5 selective small molecule inhibitor LMK-235 effectively eradicates KMT2A-rearranged ALL cell lines as well as primary patient samples in vitro. However, using a xenograft mouse model of KMT2A-rearranged ALL we found that the maximum achievable dose of LMK-235 was insufficient to induce anti-leukemic effects in vivo. Similar results were obtained for the specific class IIA HDAC inhibitors MC1568 and TMP195. Finally, LMK-235 appeared to exert minimal anti-leukemic effects in vivo in combination with the BCL-2 inhibitor venetoclax, but not enough to prolong survival in treated mice. In conclusion, class IIA HDAC isoforms represent attractive therapeutic target in KMT2A-rearranged ALL, although clinical applications require the development of more stable and efficient specific HDAC inhibitors.<br /> (© 2024. The Author(s).)

Details

Language :
English
ISSN :
2399-3642
Volume :
7
Issue :
1
Database :
MEDLINE
Journal :
Communications biology
Publication Type :
Academic Journal
Accession number :
39362994
Full Text :
https://doi.org/10.1038/s42003-024-06916-w