TY - JOUR
T1 - Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.
AU - Lewis, Alexander C.
AU - Pope, Victoria
AU - Tea, Melinda N.
AU - Li, Manjun
AU - Nwosu, Gus O.
AU - Nguyen, Thao M.
AU - Wallington-Beddoe, Associate Professor Craig T.
AU - Moretti, Paul A.
AU - Anderson, Dovile
AU - Creek, Darren J.
AU - Costabile, Maurizio
AU - Ali, Saira R.
AU - Thompson-Peach, Chloe AL.
AU - Dredge, B.
AU - Bert, Andrew G.
AU - Goodall, Gregory J.
AU - Eckert, Paul G.
AU - Brown, Anna L.
AU - D'Andrea, Richard J.
AU - Robinson, Nirmal
AU - Pitman, Melissa R.
AU - Thomas, Daniel
AU - Ross, David
AU - Gliddon, Briony L.
AU - Powell, Jason A.
AU - Pitson, Stuart M.
PY - 2022/6/30
Y1 - 2022/6/30
N2 - Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R–mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent for survival. Targeting this novel ISR pathway, in combination with the Bcl-2 inhibitor venetoclax, synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.
AB - Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R–mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent for survival. Targeting this novel ISR pathway, in combination with the Bcl-2 inhibitor venetoclax, synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.
KW - Acute Myeloid Leukemia
KW - Ceramide
KW - Bcl-2 inhibitor resistance
UR - http://purl.org/au-research/grants/NHMRC/GNT1156693
UR - http://purl.org/au-research/grants/NHMRC/PG101400
UR - http://purl.org/au-research/grants/NHMRC/GNT1145139
UR - http://purl.org/au-research/grants/NHMRC/GNT1184485
UR - http://www.scopus.com/inward/record.url?scp=85133172978&partnerID=8YFLogxK
U2 - 10.1182/blood.2021013277
DO - 10.1182/blood.2021013277
M3 - Article
SN - 0006-4971
VL - 139
SP - 3737
EP - 3751
JO - Blood
JF - Blood
IS - 26
ER -
