Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo
[Paper-level Aggregated] PMCID: PMC5629366
Evidence Type(s): Functional
Summary: Mutation: R132H | Summary: The R132H mutation alters the histone methylation phenotype in AML cells, demonstrating a change in molecular function related to histone trimethylation levels.
Gene→Variant (gene-first): IDH1(3417):R132H
Genes: IDH1(3417)
Variants: R132H
Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo
[Paper-level Aggregated] PMCID: PMC5629366
Evidence Type(s): Oncogenic
Summary: Mutation: R132C | Summary: The R132C mutation in IDH1 contributes to tumor development, supporting its classification as an oncogenic variant.
Evidence Type: Oncogenic Mutation: R132G | Summary: The R132G mutation in IDH1 is implicated in tumor development, supporting its classification as an oncogenic variant.
Evidence Type: Oncogenic Mutation: R132H | Summary: The R132H mutation in IDH1 is associated with tumor development or progression in human AML cells, indicating its oncogenic potential.
Evidence Type: Oncogenic Mutation: R132L | Summary: The R132L mutation in IDH1 contributes to tumor development, supporting its classification as an oncogenic variant.
Evidence Type: Oncogenic Mutation: R132S | Summary: The R132S mutation in IDH1 is implicated in tumor development, indicating its oncogenic potential.
Evidence Type: Oncogenic Mutation: p.D835del | Summary: The p.D835del mutation in FLT3-TKD is associated with tumor development in acute myeloid leukemia (AML) as indicated by its presence in primary AML cells.
Evidence Type: Oncogenic Mutation: p.Q61R | Summary: The p.Q61R mutation in NRAS is implicated in tumor progression in acute myeloid leukemia (AML) as it was identified as an additional aberration in the patient’s AML cells.
Gene→Variant (gene-first): IDH1(3417):R132C IDH1(3417):R132G IDH1(3417):R132H IDH1(3417):R132L IDH1(3417):R132S FLT3(2322):p.D835del NRAS(4893):p.Q61R
Genes: IDH1(3417) FLT3(2322) NRAS(4893)
Variants: R132C R132G R132H R132L R132S p.D835del p.Q61R
Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo
[Paper-level Aggregated] PMCID: PMC5629366
Evidence Type(s): Predictive
Summary: Mutation: R132C | Summary: The R132C mutation in IDH1 is associated with sensitivity to the IDH1 inhibitor BAY1436032, indicating a predictive relationship for therapy response.
Evidence Type: Predictive Mutation: R132G | Summary: The R132G mutation in IDH1 shows sensitivity to the IDH1 inhibitor BAY1436032, suggesting it is predictive of treatment response.
Evidence Type: Predictive Mutation: R132H | Summary: The R132H mutation in IDH1 correlates with sensitivity to the IDH1 inhibitor BAY1436032, indicating a predictive relationship for therapy response and is associated with treatment response in AML cells.
Evidence Type: Predictive Mutation: R132L | Summary: The R132L mutation in IDH1 is linked to sensitivity to the IDH1 inhibitor BAY1436032, suggesting a predictive relationship for treatment response.
Evidence Type: Predictive Mutation: R132S | Summary: The R132S mutation in IDH1 is associated with sensitivity to the IDH1 inhibitor BAY1436032, indicating a predictive relationship for therapy response.
Gene→Variant (gene-first): IDH1(3417):R132C IDH1(3417):R132G IDH1(3417):R132H IDH1(3417):R132L IDH1(3417):R132S
Genes: IDH1(3417)
Variants: R132C R132G R132H R132L R132S
In addition to histone hypermethylation, human AML cells with IDH1/IDH2 mutation show global DNA hypermethylation. To test whether treatment with BAY1436032 alters DNA methylation, primary human AML cells carrying either
[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 18
Evidence Type(s): Predictive, Oncogenic
Summary: Evidence Type: Predictive | Mutation: R132H | Summary: The R132H mutation in IDH1 is associated with treatment response to BAY1436032, indicating a correlation with sensitivity to this specific therapy. Evidence Type: Oncogenic | Mutation: R132H | Summary: The R132H mutation contributes to tumor development or progression in human AML cells, as indicated by its presence in the context of IDH1/IDH2 mutations.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
The inhibition of histone demethylases by R-2HG results in a histone hypermethylation phenotype. Accordingly, global histone H3 trimethylation levels at residues H3K4, H3K9, H3K27 and H3K36 were analyzed ex vivo by immun
[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 17
Evidence Type(s): Predictive, Functional
Summary: Evidence Type: Predictive | Mutation: R132H | Summary: The R132H mutation in IDH1 is associated with sensitivity to the treatment with BAY1436032, indicating a correlation with therapeutic response in AML cells. Evidence Type: Functional | Mutation: R132H | Summary: The R132H mutation alters the histone methylation phenotype in AML cells, demonstrating a change in molecular function related to histone trimethylation levels.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
A PDX mouse model was developed using primary AML cells from a patient with IDH1R132C mutant AML (PDX1). Targeted sequencing of the patient AML cells revealed a FLT3-TKD (p.D835del), an atypical NPM1 (p.S254LfsTer4), and
[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: p.D835del | Summary: The p.D835del mutation in FLT3-TKD is associated with tumor development in acute myeloid leukemia (AML) as indicated by its presence in primary AML cells. Evidence Type: Oncogenic | Mutation: p.Q61R | Summary: The p.Q61R mutation in NRAS is implicated in tumor progression in acute myeloid leukemia (AML) as it was identified as an additional aberration in the patient’s AML cells.
Gene→Variant (gene-first): 2322:p.D835del 4893:p.Q61R
Genes: 2322 4893
Variants: p.D835del p.Q61R
We developed a novel IDH1 inhibitor, BAY1436032, with high selectivity against all known IDH1R132 mutant proteins (R132H, R132C, R132G, R132S and R132L) compared to wild-type IDH1 and wild-type or mutant IDH2. Details on
[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Summary: Evidence Type: Predictive | Mutation: R132C | Summary: The R132C mutation in IDH1 is associated with sensitivity to the IDH1 inhibitor BAY1436032, indicating a predictive relationship for therapy response. Evidence Type: Predictive | Mutation: R132G | Summary: The R132G mutation in IDH1 shows sensitivity to the IDH1 inhibitor BAY1436032, suggesting it is predictive of treatment response. Evidence Type: Predictive | Mutation: R132H | Summary: The R132H mutation in IDH1 correlates with sensitivity to the IDH1 inhibitor BAY1436032, indicating a predictive relationship for therapy response. Evidence Type: Predictive | Mutation: R132L | Summary: The R132L mutation in IDH1 is linked to sensitivity to the IDH1 inhibitor BAY1436032, suggesting a predictive relationship for treatment response. Evidence Type: Predictive | Mutation: R132S | Summary: The R132S mutation in IDH1 is associated with sensitivity to the IDH1 inhibitor BAY1436032, indicating a predictive relationship for therapy response. Evidence Type: Oncogenic | Mutation: R132C | Summary: The R132C mutation in IDH1 contributes to tumor development, supporting its classification as an oncogenic variant. Evidence Type: Oncogenic | Mutation: R132G | Summary: The R132G mutation in IDH1 is implicated in tumor development, supporting its classification as an oncogenic variant. Evidence Type: Oncogenic | Mutation: R132H | Summary: The R132H mutation in IDH1 is associated with tumor development, indicating its oncogenic potential. Evidence Type: Oncogenic | Mutation: R132L | Summary: The R132L mutation in IDH1 contributes to tumor development, supporting its classification as an oncogenic variant. Evidence Type: Oncogenic | Mutation: R132S | Summary: The R132S mutation in IDH1 is implicated in tumor development, indicating its oncogenic potential.
Gene→Variant (gene-first): 3417:R132C 3417:R132G 3417:R132H 3417:R132L 3417:R132S 3418:R140Q
Genes: 3417 3418
Variants: R132C R132G R132H R132L R132S R140Q
Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo
[Paper-level Aggregated] PMCID: PMC5629366
Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic
Justification: Oncogenic: The text discusses the development of a novel IDH1 inhibitor targeting various IDH1R132 mutations, indicating that these mutations are associated with oncogenic activity in AML cells. Functional: The evidence shows that BAY1436032 inhibits the enzymatic function of mutant IDH1 proteins and alters histone and DNA methylation patterns in AML cells, demonstrating a functional impact on cellular processes. Predictive: The sensitivity of patient-derived AML cells with IDH1R132 mutations to BAY1436032 suggests that these mutations can predict the efficacy of the treatment. Prognostic: The presence of IDH1R132 mutations and their response to BAY1436032 may provide prognostic information regarding the potential outcomes in AML patients treated with this inhibitor.
Gene→Variant (gene-first): IDH1(3417):R132C IDH1(3417):R132G IDH1(3417):R132H IDH1(3417):R132L IDH1(3417):R132S IDH2(3418):R140Q FLT3(2322):p.D835del NRAS(4893):p.Q61R
Genes: IDH1(3417) IDH2(3418) FLT3(2322) NRAS(4893)
Variants: R132C R132G R132H R132L R132S R140Q p.D835del p.Q61R
In addition to histone hypermethylation, human AML cells with IDH1/IDH2 mutation show global DNA hypermethylation. To test whether treatment with BAY1436032 alters DNA methylation, primary human AML cells carrying either
[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 18
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the treatment of AML cells with BAY1436032 and its effects on DNA methylation, indicating a correlation between the IDH1R132H mutation and the response to this specific therapy. Functional: The passage describes how the IDH1R132H mutation affects DNA methylation patterns and gene expression, demonstrating an alteration in molecular function due to the variant.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
The inhibition of histone demethylases by R-2HG results in a histone hypermethylation phenotype. Accordingly, global histone H3 trimethylation levels at residues H3K4, H3K9, H3K27 and H3K36 were analyzed ex vivo by immun
[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 17
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the response of IDH1 mutant AML cells, including those with the R132H mutation, to the treatment with BAY1436032, indicating a correlation with therapy response. Functional: The passage describes how the R132H variant alters histone methylation levels, demonstrating a change in molecular function related to histone demethylation.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
A PDX mouse model was developed using primary AML cells from a patient with IDH1R132C mutant AML (PDX1). Targeted sequencing of the patient AML cells revealed a FLT3-TKD (p.D835del), an atypical NPM1 (p.S254LfsTer4), and
[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the treatment of PDX models with BAY1436032, indicating a correlation between the variant mutations and the response to this specific therapy. Oncogenic: The passage describes the presence of somatic mutations (p.D835del and p.Q61R) in AML cells that contribute to tumor development, as evidenced by their propagation in PDX models.
Gene→Variant (gene-first): 2322:p.D835del 4893:p.Q61R
Genes: 2322 4893
Variants: p.D835del p.Q61R
We developed a novel IDH1 inhibitor, BAY1436032, with high selectivity against all known IDH1R132 mutant proteins (R132H, R132C, R132G, R132S and R132L) compared to wild-type IDH1 and wild-type or mutant IDH2. Details on
[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of various IDH1R132 mutant proteins to the IDH1 inhibitor BAY1436032, indicating a correlation between the presence of these variants and the response to the therapy. Oncogenic: The variants mentioned (R132C, R132G, R132H, R132L, R132S) are associated with mutant IDH1 proteins that contribute to tumor development, as evidenced by their expression in patient-derived AML cells and their role in producing R-2HG.
Gene→Variant (gene-first): 3417:R132C 3417:R132G 3417:R132H 3417:R132L 3417:R132S 3418:R140Q
Genes: 3417 3418
Variants: R132C R132G R132H R132L R132S R140Q