[Paper-level Aggregated] PMCID: PMC4675689

Evidence Type(s): Functional

Summary: Mutation: D835 | Summary: The D835 mutation is critical for stabilizing the inactive conformation of FLT3, impacting molecular interactions necessary for type II inhibitor binding. It plays a role in stabilizing the DFG-out conformation of the kinase and affects the short alpha-helix coupled to the drug-binding site.

Evidence Type: Functional Mutation: D835E/N | Summary: The D835E/N mutations are predicted to preserve hydrogen bonding interactions that maintain the structural integrity of the protein, suggesting an alteration in molecular function related to inhibitor binding and preserving critical structural features necessary for the binding of type II inhibitors.

Evidence Type: Functional Mutation: D835Y | Summary: The D835Y mutation alters molecular interactions due to large and bulky hydrophobic amino acid residues, affecting hydrogen bonding and steric compatibility.

Evidence Type: Functional Mutation: D835V | Summary: The D835V mutation is characterized by large and bulky hydrophobic amino acid residues, impacting molecular interactions and steric compatibility with the protein structure.

Evidence Type: Functional Mutation: D835H | Summary: The D835H mutation alters molecular interactions, specifically affecting hydrogen bond formation and binding mode accommodation, which impacts its biochemical function.

Evidence Type: Functional Mutation: D835N/E | Summary: The D835N/E mutations preserve critical structural features necessary for the binding of type II inhibitors, affecting the molecular function of FLT3.

Gene→Variant (gene-first): FLT3(2322):D835 FLT3(2322):D835E/N NA:D835Y NA:D835V FLT3(2322):D835H FLT3(2322):D835N/E

Genes: FLT3(2322) NA

Variants: D835 D835E/N D835Y D835V D835H D835N/E

[Paper-level Aggregated] PMCID: PMC4675689

Evidence Type(s): Oncogenic

Summary: Mutation: D835 | Summary: The D835 mutation contributes to tumor development by influencing the kinase's conformation and resistance to inhibitors.

Evidence Type: Oncogenic Mutation: D835V/Y/F | Summary: The D835V/Y/F mutations are implicated in clinical resistance to FLT3 inhibitors, supporting their oncogenic potential.

Evidence Type: Oncogenic Mutation: D835H | Summary: The D835H mutation has been observed in clinical resistance to sorafenib, suggesting its role in tumor progression.

Evidence Type: Oncogenic Mutation: D835A/E/G/N | Summary: The D835A/E/G/N mutations are associated with lower resistance to FLT3 inhibitors, suggesting their involvement in tumor behavior.

Evidence Type: Oncogenic Mutation: D835E/N | Summary: The D835E/N mutations contribute to tumor development by preserving the DFG-out conformation, which is associated with sensitivity to type II inhibitors, indicating a role in cancer progression.

Evidence Type: Oncogenic Mutation: D835N/E | Summary: The D835N/E mutations are implicated in tumor progression by maintaining a conformation that allows for continued kinase activity despite treatment.

Gene→Variant (gene-first): FLT3(2322):D835 NA:D835V/Y/F FLT3(2322):D835H NA:D835A/E/G/N FLT3(2322):D835E/N FLT3(2322):D835N/E

Genes: FLT3(2322) NA

Variants: D835 D835V/Y/F D835H D835A/E/G/N D835E/N D835N/E

[Paper-level Aggregated] PMCID: PMC4675689

Evidence Type(s): Predictive

Summary: Mutation: D835 | Summary: The D835 mutation is associated with resistance to FLT3 tyrosine kinase inhibitors (TKIs) and type II inhibitors, indicating its predictive value for therapy response.

Evidence Type: Predictive Mutation: D835V/Y/F | Summary: The D835V/Y/F mutations are linked to a high degree of resistance to type II FLT3 inhibitors, indicating their predictive value for therapy response.

Evidence Type: Predictive Mutation: D835H | Summary: The D835H mutation is associated with intermediate resistance to sorafenib and type II inhibitors, indicating its predictive value for therapy response.

Evidence Type: Predictive Mutation: D835A/E/G/N | Summary: The D835A/E/G/N mutations conferred the least degree of resistance to type II inhibitors, indicating their predictive value for therapy response.

Evidence Type: Predictive Mutation: D835N/E | Summary: The D835N/E mutations may retain sensitivity to type II FLT3 TKIs, indicating a potential response to therapy.

Gene→Variant (gene-first): FLT3(2322):D835 NA:D835V/Y/F FLT3(2322):D835H NA:D835A/E/G/N FLT3(2322):D835N/E

Genes: FLT3(2322) NA

Variants: D835 D835V/Y/F D835H D835A/E/G/N D835N/E

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Functional, Oncogenic

Summary: Evidence Type: Predictive | Mutation: D835 | Summary: The D835 mutation is associated with sensitivity to type II inhibitors, suggesting that certain D835 mutants may respond to therapy despite being excluded from clinical trials. Evidence Type: Functional | Mutation: D835 | Summary: The D835 residue is critical for stabilizing the inactive conformation of FLT3, and mutations at this site affect the molecular interactions necessary for type II inhibitor binding. Evidence Type: Oncogenic | Mutation: D835 | Summary: The D835 mutation contributes to tumor development by influencing the kinase's conformation and resistance to inhibitors. Evidence Type: Predictive | Mutation: D835N/E | Summary: The D835N/E mutations may retain sensitivity to type II FLT3 TKIs, indicating a potential response to therapy. Evidence Type: Functional | Mutation: D835N/E | Summary: The D835N/E mutations preserve critical structural features necessary for the binding of type II inhibitors, affecting the molecular function of FLT3. Evidence Type: Oncogenic | Mutation: D835N/E | Summary: The D835N/E mutations are implicated in tumor progression by maintaining a conformation that allows for continued kinase activity despite treatment.

Gene→Variant (gene-first): 2322:D835 2322:D835N/E

Genes: 2322

Variants: D835 D835N/E

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: D835H | Summary: The D835H mutation is associated with resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Evidence Type: Functional | Mutation: D835H | Summary: The D835H mutation alters molecular interactions, specifically affecting hydrogen bond formation and binding mode accommodation, which impacts its biochemical function.

Gene→Variant (gene-first): 2322:D835H

Genes: 2322

Variants: D835H

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D835Y | Summary: The D835Y mutation alters molecular interactions, as it is described as having large and bulky hydrophobic amino acid residues that affect hydrogen bonding and steric compatibility. Evidence Type: Functional | Mutation: D835V | Summary: The D835V mutation is characterized by large and bulky hydrophobic amino acid residues, impacting molecular interactions and steric compatibility with the protein structure.

Gene→Variant (gene-first): 2322:D835Y/V

Genes: 2322

Variants: D835Y/V

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: D835E/N | Summary: The D835E/N mutations are predicted to preserve hydrogen bonding interactions that maintain the structural integrity of the protein, suggesting an alteration in molecular function related to inhibitor binding. Evidence Type: Oncogenic | Mutation: D835E/N | Summary: The D835E/N mutations contribute to tumor development by preserving the DFG-out conformation, which is associated with sensitivity to type II inhibitors, indicating a role in cancer progression.

Gene→Variant (gene-first): 2322:D835 2322:D835E/N

Genes: 2322

Variants: D835 D835E/N

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: D835 | Summary: The D835 mutation is associated with resistance to type II inhibitors, suggesting a correlation with treatment response or resistance. Evidence Type: Functional | Mutation: D835 | Summary: The D835 mutation impacts the short alpha-helix, which is coupled to the drug-binding site, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D835 | Summary: The D835 mutation is predicted to play a critical role in stabilizing the DFG-out conformation of the kinase AL by serving as an amino-terminal capping residue for a short alpha-helix, indicating its impact on molecular function.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: D835 | Summary: The D835 mutation is associated with resistance to FLT3 tyrosine kinase inhibitors (TKIs), indicating its predictive value for therapy response. Evidence Type: Oncogenic | Mutation: D835 | Summary: D835 substitutions are reported to contribute to FLT3 TKI resistance, suggesting their role in tumor development and progression. Evidence Type: Predictive | Mutation: D835V/Y/F | Summary: The D835V/Y/F mutations are linked to a high degree of resistance to type II FLT3 inhibitors, indicating their predictive value for therapy response. Evidence Type: Oncogenic | Mutation: D835V/Y/F | Summary: The D835V/Y/F mutations are implicated in clinical resistance to FLT3 inhibitors, supporting their oncogenic potential. Evidence Type: Predictive | Mutation: D835H | Summary: The D835H mutation is associated with intermediate resistance to sorafenib, indicating its predictive value for therapy response. Evidence Type: Oncogenic | Mutation: D835H | Summary: The D835H mutation has been observed in clinical resistance to sorafenib, suggesting its role in tumor progression. Evidence Type: Predictive | Mutation: D835A/E/G/N | Summary: The D835A/E/G/N mutations conferred the least degree of resistance to type II inhibitors, indicating their predictive value for therapy response. Evidence Type: Oncogenic | Mutation: D835A/E/G/N | Summary: The D835A/E/G/N mutations are associated with lower resistance to FLT3 inhibitors, suggesting their involvement in tumor behavior.

Gene→Variant (gene-first): 2322:D835 2322:D835A/E 2322:D835H 2322:D835V/Y

Genes: 2322

Variants: D835 D835A/E D835H D835V/Y

[Paper-level Aggregated] PMCID: PMC4675689

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The D835 mutations are reported to cause FLT3 TKI resistance in patients, indicating their role in tumorigenesis and cancer progression. Predictive: The study suggests that specific D835 mutations can predict the level of resistance to type II FLT3 inhibitors, which can inform treatment decisions. Functional: The text discusses the functional implications of D835 mutations on the stability of the DFG-out conformation and their impact on inhibitor binding, demonstrating the functional consequences of these mutations.

Gene→Variant (gene-first): FLT3(2322):D835 FLT3(2322):D835A/E FLT3(2322):D835H FLT3(2322):D835V/Y FLT3(2322):D835E/N FLT3(2322):D835N/E FLT3(2322):D835Y/V

Genes: FLT3(2322)

Variants: D835 D835A/E D835H D835V/Y D835E/N D835N/E D835Y/V

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of D835 mutants to type II inhibitors, indicating a correlation with treatment response, which aligns with predictive evidence. Oncogenic: The mention of D835 mutations and their role in mediating resistance and sensitivity to FLT3 TKIs suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2322:D835 2322:D835N/E

Genes: 2322

Variants: D835 D835N/E

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the D835H mutation's resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Functional: The passage describes how the D835H mutation alters the binding mode and hydrogen bond formation, indicating a change in molecular function related to inhibitor interaction.

Gene→Variant (gene-first): 2322:D835H

Genes: 2322

Variants: D835H

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the D835Y/V variant alters molecular interactions and structural compatibility, indicating a change in biochemical function related to steric hindrance and hydrogen bonding. Oncogenic: The mention of "highly resistant mutants" suggests that the D835Y/V variant contributes to tumor development or progression by conferring resistance, which is characteristic of oncogenic behavior.

Gene→Variant (gene-first): 2322:D835Y/V

Genes: 2322

Variants: D835Y/V

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the D835E/N mutations alter molecular interactions, specifically the formation of hydrogen bonds and the conservation of the alpha-helix structure, which affects inhibitor binding. Predictive: The passage indicates that the D835E/N variants are associated with sensitivity to type II inhibitors, suggesting a correlation with treatment response.

Gene→Variant (gene-first): 2322:D835 2322:D835E/N

Genes: 2322

Variants: D835 D835E/N

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the correlation of D835 mutations with resistance to type II inhibitors, indicating a relationship between the variant and treatment response. Functional: The passage describes the impact of D835 mutations on the short alpha-helix and its potential effect on the drug-binding site, suggesting an alteration in molecular function related to drug interaction.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the D835 variant alters the molecular function of the kinase by stabilizing the DFG-out conformation and forming interactions that affect the structure of the alpha-helix.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how various D835 substitutions correlate with resistance to FLT3 inhibitors, indicating their predictive value regarding treatment response. Oncogenic: The D835 mutations are reported to cause resistance in patients, suggesting that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2322:D835 2322:D835A/E 2322:D835H 2322:D835V/Y

Genes: 2322

Variants: D835 D835A/E D835H D835V/Y

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of D835 mutants to type II inhibitors, indicating a correlation with treatment response, which aligns with predictive evidence. Oncogenic: The mention of D835 mutations and their role in mediating resistance and sensitivity to FLT3 TKIs suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2322:D835 2322:D835N/E

Genes: 2322

Variants: D835 D835N/E

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the D835H mutation's resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Functional: The passage describes how the D835H mutation alters the binding mode and hydrogen bond formation, indicating a change in molecular function related to inhibitor interaction.

Gene→Variant (gene-first): 2322:D835H

Genes: 2322

Variants: D835H

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the D835Y/V variant alters molecular interactions and structural compatibility, indicating a change in biochemical function related to steric hindrance and hydrogen bonding. Oncogenic: The mention of "highly resistant mutants" suggests that the D835Y/V variant contributes to tumor development or progression by conferring resistance, which is characteristic of oncogenic behavior.

Gene→Variant (gene-first): 2322:D835Y/V

Genes: 2322

Variants: D835Y/V

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the D835E/N mutations alter molecular interactions, specifically the formation of hydrogen bonds and the conservation of the alpha-helix structure, which affects inhibitor binding. Predictive: The passage indicates that the D835E/N variants are associated with sensitivity to type II inhibitors, suggesting a correlation with treatment response.

Gene→Variant (gene-first): 2322:D835 2322:D835E/N

Genes: 2322

Variants: D835 D835E/N

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the correlation of D835 mutations with resistance to type II inhibitors, indicating a relationship between the variant and treatment response. Functional: The passage describes the impact of D835 mutations on the short alpha-helix and its potential effect on the drug-binding site, suggesting an alteration in molecular function related to drug interaction.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the D835 variant alters the molecular function of the kinase by stabilizing the DFG-out conformation and forming interactions that affect the structure of the alpha-helix.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how various D835 substitutions correlate with resistance to FLT3 inhibitors, indicating their predictive value regarding treatment response. Oncogenic: The D835 mutations are reported to cause resistance in patients, suggesting that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2322:D835 2322:D835A/E 2322:D835H 2322:D835V/Y

Genes: 2322

Variants: D835 D835A/E D835H D835V/Y