ORCID Profile
0000-0002-5363-9081
Current Organisation
INRA Centre de Toulouse Midi-Pyrénées
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Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618428
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641326
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618425
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641323
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618422
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641311.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641329
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641305.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618467.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579646.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641287
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641320
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579598.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641284
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641320.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579643
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.C.6713553.V3
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-7-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1501 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641317
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641314.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641314
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.C.6713553.V1
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. /
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579640
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.C.6713553.V2
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618437
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618434
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641311
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618431
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579637.V1
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618464.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579643.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641308.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579649
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579646
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618449
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579625.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579631.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618446
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641317.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618443
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618440
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618470.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579640.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641332.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641326.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579628.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641338
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618458
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641299
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641332
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579634.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618455
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618431.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618452
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641290
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641323.V1
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618428.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641296
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579604.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579610
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.C.6713553
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-7-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1501 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641338.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618467
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618464
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618461
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641296.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618434.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618437.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579613.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579616
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618440.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579613
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618425.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618446.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579622.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641299.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579601.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618470
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579616.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.CD-22-0411
Abstract: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641329.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618443.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579607
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579604
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579601
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618422.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641305
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579631
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618449.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579598
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641302
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618455.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-0001
DOI: 10.1158/2159-8290.23641308
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618461.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618458.V1
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579637
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641284.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579634
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579649.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579607.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618452.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641290.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641302.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579628
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641287.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579610.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579625
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579622
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Hervé Guillou.