Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia.

Abstract

While oncogenes promote tumorigenesis, they also induce deleterious cellular stresses, such as apoptosis, that cancer cells must combat by coopting adaptive responses. Whether tumor suppressor gene haploinsufficiency leads to such phenomena and their mechanistic basis is unclear. Here, we demonstrate that elevated levels of the anti-apoptotic factor, CASP8 and FADD-like apoptosis regulator (CFLAR), promotes apoptosis evasion in acute myeloid leukemia (AML) cells haploinsufficient for the cut-like homeobox 1 (CUX1) transcription factor, whose loss is associated with dismal clinical prognosis. Genome-wide CRISPR/Cas9 screening identifies CFLAR as a selective, acquired vulnerability in CUX1-deficient AML, which can be mimicked therapeutically using inhibitor of apoptosis (IAP) antagonists in murine and human AML cells. Mechanistically, CUX1 deficiency directly alleviates CUX1 repression of the CFLAR promoter to drive CFLAR expression and leukemia survival. These data establish how haploinsufficiency of a tumor suppressor is sufficient to induce advantageous anti-apoptosis cell survival pathways and concurrently nominate CFLAR as potential therapeutic target in these poor-prognosis leukemias.

• Authors: Emmanuelle Supper, Saskia Rudat, Vivek Iyer, Alastair Droop, Kim Wong, Jean-François Spinella, Patrick Thomas, Guy Sauvageau, David J Adams, Chi C Wong
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 2482 (04 30 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33931647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• Cux1 protein, mouse
• Dipeptides
• Homeodomain Proteins
• Indoles
• Nuclear Proteins
• Repressor Proteins
• birinapant
• fms-Like Tyrosine Kinase 3

Topics

• Animals
• Apoptosis (drug effects, genetics)
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Cell Survival (genetics)
• Chromatin Immunoprecipitation
• Dipeptides (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Gene Ontology
• Genes, Tumor Suppressor
• Haploinsufficiency
• Hematopoietic Stem Cells (metabolism)
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Indoles (pharmacology)
• Kaplan-Meier Estimate
• Leukemia, Myeloid, Acute (genetics, metabolism, mortality, pathology)
• Leukemia, Myelomonocytic, Chronic (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation
• Nuclear Proteins (deficiency, genetics, metabolism)
• Promoter Regions, Genetic
• Protein Array Analysis
• Repressor Proteins (deficiency, genetics, metabolism)
• fms-Like Tyrosine Kinase 3 (genetics, metabolism)