ORCID Profile
0000-0003-2093-1403
Current Organisations
Walter and Eliza Hall Institute of Medical Research
,
Monash University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
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: Springer Science and Business Media LLC
Date: 29-06-2012
DOI: 10.1038/CDD.2012.84
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: Cold Spring Harbor Laboratory
Date: 18-03-2022
DOI: 10.1101/2022.03.16.483971
Abstract: Iron is mostly devoted to the hemoglobinization of erythrocytes for oxygen transport. Yet, emerging evidence points to a broader role for the metal in hematopoiesis, including the formation of the immune system. Iron availability in mammalian cells is controlled by iron-regulatory proteins (IRP)-1 and −2. We report that global disruption of both IRP1 and IRP2 in adult mice impairs neutrophil development and differentiation in the bone marrow, yielding immature neutrophils with abnormally high glycolytic and autophagic activity, resulting in neutropenia. IRPs promote neutrophil differentiation in a cell intrinsic manner by securing cellular iron supply together with transcriptional control of neutropoiesis to facilitate differentiation to fully mature neutrophils. Unlike neutrophils, monocyte count was not affected by IRP and iron deficiency, suggesting a lineage-specific effect of iron on myeloid output. This study unveils the previously unrecognized importance of IRPs and iron metabolism in the formation of a major branch of the innate immune system.
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: Springer Science and Business Media LLC
Date: 09-2016
Abstract: Inhibition of the apoptosis pathway controlled by opposing members of the Bcl-2 protein family plays a central role in cancer development and resistance to therapy. To investigate how pro-apoptotic Bcl-2 homology domain 3 (BH3)-only proteins impact on acute myeloid leukemia (AML), we generated mixed lineage leukemia ( MLL)-AF9 and MLL-ENL AMLs from BH3-only gene knockout mice. Disease development was not accelerated by loss of Bim, Puma, Noxa, Bmf, or combinations thereof hence these BH3-only proteins are apparently ineffectual as tumor suppressors in this model. We tested the sensitivity of MLL-AF9 AMLs of each genotype in vitro to standard chemotherapeutic drugs and to the proteasome inhibitor bortezomib, with or without the BH3 mimetic ABT-737. Loss of Puma and/or Noxa increased resistance to cytarabine, daunorubicin and etoposide, while loss of Bim protected against cytarabine and loss of Bmf had no impact. ABT-737 increased sensitivity to the genotoxic drugs but was not dependent on any BH3-only protein tested. The AML lines were very sensitive to bortezomib and loss of Noxa conveyed significant resistance. In vivo, several MLL-AF9 AMLs responded well to daunorubicin and this response was highly dependent on Puma and Noxa but not Bim. Combination therapy with ABT-737 provided little added benefit at the daunorubicin dose trialed. Bortezomib also extended survival of AML-bearing mice, albeit less than daunorubicin. In summary, our genetic studies reveal the importance of Puma and Noxa for the action of genotoxics currently used to treat MLL-driven AML and suggest that, while addition of ABT-737-like BH3 mimetics might enhance their efficacy, new Noxa-like BH3 mimetics targeting Mcl-1 might have greater potential.
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: Springer Science and Business Media LLC
Date: 11-08-2017
DOI: 10.1038/CDD.2017.131
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: 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: 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: 10.1158/2159-8290.23579640
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 Society of Hematology
Date: 09-02-2023
Abstract: Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML.
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: Springer Science and Business Media LLC
Date: 31-03-2017
DOI: 10.1038/CDD.2017.30
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: Springer Science and Business Media LLC
Date: 16-01-2018
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 Society of Hematology
Date: 12-2022
Publisher: American Society of Hematology
Date: 20-05-2021
Abstract: Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across erse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are in idually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.
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: Rockefeller University Press
Date: 16-04-2020
DOI: 10.1084/JEM.20191284
Abstract: The proliferative activity of aging hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that primitive HSCs symmetrically ide only four times to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in HSCs with high repopulation potential. We argue that this background had been misinterpreted as stable retention of induced label. We found cell ision–independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC isional activity. Our data do not support abrupt entry of HSCs into permanent quiescence or sudden loss of regeneration potential after four isions, but show that primitive HSCs of adult mice continue to cycle rarely.
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: Springer Science and Business Media LLC
Date: 04-11-2016
DOI: 10.1038/CDD.2016.125
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: 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: 10.1158/2159-8290.23579604
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: 26-06-2023
DOI: 10.1158/2159-8290.23579598
Abstract: Table S9: CEBPA_UP signature
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: 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: Springer Science and Business Media LLC
Date: 23-11-2019
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: Springer Science and Business Media LLC
Date: 04-2019
DOI: 10.1038/S41591-019-0379-5
Abstract: Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.
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 Society of Hematology
Date: 24-01-2020
Abstract: Deregulated over-expression of MYC is implicated in the development and malignant progression of most (~70%) human tumors. MYC drives cell growth and proliferation but also, at high levels, promotes apoptosis. Here, we report that the proliferative capacity of MYC-driven normal and neoplastic B lymphoid cells depends on MNT, a MYC-related transcriptional repressor. Our genetic data establish that MNT synergises with MYC by suppressing MYC-driven apoptosis and that it does so primarily by reducing the level of pro-apoptotic BIM. In Em-Myc mice, which model the MYC/IGH chromosome translocation in Burkitt's lymphoma, homozygous Mnt deletion greatly reduced lymphoma incidence by enhancing apoptosis and markedly decreasing premalignant B lymphoid cell populations. Strikingly, by inducing Mnt deletion within transplanted fully-malignant Em-Myc lymphoma cells, we significantly extended transplant recipient survival. The dependency of lymphomas on MNT for survival suggests that drugs inhibiting MNT could significantly boost therapy of MYC-driven tumors by enhancing intrinsic MYC-driven apoptosis.
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 the Advancement of Science (AAAS)
Date: 07-10-2022
Abstract: Iron is mostly devoted to the hemoglobinization of erythrocytes for oxygen transport. However, emerging evidence points to a broader role for the metal in hematopoiesis, including the formation of the immune system. Iron availability in mammalian cells is controlled by iron-regulatory protein 1 (IRP1) and IRP2. We report that global disruption of both IRP1 and IRP2 in adult mice impairs neutrophil development and differentiation in the bone marrow, yielding immature neutrophils with abnormally high glycolytic and autophagic activity, resulting in neutropenia. IRPs promote neutrophil differentiation in a cell intrinsic manner by securing cellular iron supply together with transcriptional control of neutropoiesis to facilitate differentiation to fully mature neutrophils. Unlike neutrophils, monocyte count was not affected by IRP and iron deficiency, suggesting a lineage-specific effect of iron on myeloid output. This study unveils the previously unrecognized importance of IRPs and iron metabolism in the formation of a major branch of the innate immune system.
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: Australia
No related grants have been discovered for Natasha Anstee.