Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

Denis E. Reyna, Thomas P. Garner, Andrea Lopez, Felix Kopp, Gaurav S. Choudhary, Ashwin Sridharan, Swathi-Rao Narayanagari, Kelly Mitchell, Baoxia Dong, Boris A. Bartholdy, Loren D. Walensky, Amit K. Verma, Ulrich G. Steidl, Evripidis Gavathiotis

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The BCL-2 family protein BAX is a central mediator of apoptosis. Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators. We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells. BAX expression levels and cytosolic conformation regulate sensitivity to BTSA1. BTSA1 potently suppressed human acute myeloid leukemia (AML) xenografts and increased host survival without toxicity. This study provides proof-of-concept for direct BAX activation as a treatment strategy in AML. Reyna et al. develop BTSA1, a pharmacologically optimized BAX activator, and show that BTSA1-induced BAX activation effectively and selectively promotes apoptosis of acute myeloid leukemia cells. They further demonstrate that the BAX expression level and cytosolic conformation regulate the sensitivity to BTSA1.

Original languageEnglish (US)
Pages (from-to)490-505.e10
JournalCancer Cell
Volume32
Issue number4
DOIs
StatePublished - Oct 9 2017

Fingerprint

Acute Myeloid Leukemia
Apoptosis
Myeloid Cells
Heterografts
Leukemia
Proteins
Cell Line
Survival
Therapeutics
Neoplasms

Keywords

  • apoptosis
  • BAX
  • BAX activator
  • BCL-2 family
  • BH3
  • BTSA1
  • cell death
  • leukemia
  • mitochondria
  • MOMP

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia. / Reyna, Denis E.; Garner, Thomas P.; Lopez, Andrea; Kopp, Felix; Choudhary, Gaurav S.; Sridharan, Ashwin; Narayanagari, Swathi-Rao; Mitchell, Kelly; Dong, Baoxia; Bartholdy, Boris A.; Walensky, Loren D.; Verma, Amit K.; Steidl, Ulrich G.; Gavathiotis, Evripidis.

In: Cancer Cell, Vol. 32, No. 4, 09.10.2017, p. 490-505.e10.

Research output: Contribution to journalArticle

Reyna, Denis E. ; Garner, Thomas P. ; Lopez, Andrea ; Kopp, Felix ; Choudhary, Gaurav S. ; Sridharan, Ashwin ; Narayanagari, Swathi-Rao ; Mitchell, Kelly ; Dong, Baoxia ; Bartholdy, Boris A. ; Walensky, Loren D. ; Verma, Amit K. ; Steidl, Ulrich G. ; Gavathiotis, Evripidis. / Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia. In: Cancer Cell. 2017 ; Vol. 32, No. 4. pp. 490-505.e10.
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