Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
[Paper-level Aggregated] PMCID: PMC5820258
Evidence Type(s): Functional
Summary: Mutation: p.W110 | Summary: The p.W110 mutation in CDKN2A/B is a nonsense mutation that likely alters the molecular function of the gene, contributing to cancer-related processes.
Gene→Variant (gene-first): TP53(7157):p.W110*
Genes: TP53(7157)
Variants: p.W110*
Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
[Paper-level Aggregated] PMCID: PMC5820258
Evidence Type(s): Oncogenic
Summary: Mutation: p.K601E | Summary: The BRAF p.K601E mutation is described as oncogenic and contributes to tumor development and progression, making it a target for therapies such as MEK inhibitors. It was retained in the subclone that emerged during venetoclax therapy.
Evidence Type: Oncogenic Mutation: p.Q36H | Summary: The BTG1 missense mutation p.Q36H may contribute to tumor development or progression in CLL cells under targeted BCL2-inhibition, providing a survival advantage. It is part of a branch observed only in the relapse sample, suggesting its contribution to tumor evolution and progression.
Evidence Type: Oncogenic Mutation: p.E46K | Summary: The p.E46K mutation in BTG1 contributes to tumor evolution and is selected as a dominant clone, indicating its role in tumor progression. It may also contribute to tumor development or progression in CLL cells under targeted BCL2-inhibition.
Evidence Type: Oncogenic Mutation: p.S321fs | Summary: The mutation p.S321fs in MLL3 is implicated in tumor development, as it was present in the subclone that persisted through treatment.
Evidence Type: Oncogenic Mutation: p.Q547fs | Summary: The frameshift deletion p.Q547fs in BIRC3 is recognized as a driver mutation in CLL, contributing to tumorigenesis.
Evidence Type: Oncogenic Mutation: c.1996A > C | Summary: The SF3B1 mutation c.1996A > C was identified in cancer cell subclones that evolved during venetoclax exposure, indicating its contribution to tumor development and progression.
Evidence Type: Oncogenic Mutation: c.1997A > C | Summary: The SF3B1 mutation c.1997A > C was found in subclones that emerged during treatment with venetoclax, suggesting its role in tumor development and progression.
Evidence Type: Oncogenic Mutation: p.K666Q | Summary: The mutation p.K666Q was detected in small subclones before treatment and evolved during venetoclax therapy, indicating its involvement in oncogenic processes.
Evidence Type: Oncogenic Mutation: p.K666T | Summary: The mutation p.K666T was present in subclones that evolved during venetoclax exposure, supporting its role in tumor development and progression.
Evidence Type: Oncogenic Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development and progression, as evidenced by its role in inducing venetoclax resistance in cell lines.
Gene→Variant (gene-first): BRAF(673):p.K601E BTG1(694):p.Q36H TP53(7157):p.E46K KMT2C(58508):p.S321fs BIRC3(330):p.Q547fs SF3B1(23451):c.1996A > C SF3B1(23451):c.1997A > C SF3B1(23451):p.K666Q SF3B1(23451):p.K666T BRAF(673):BRAFV600E
Genes: BRAF(673) BTG1(694) TP53(7157) KMT2C(58508) BIRC3(330) SF3B1(23451)
Variants: p.K601E p.Q36H p.E46K p.S321fs p.Q547fs c.1996A > C c.1997A > C p.K666Q p.K666T BRAFV600E
Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
[Paper-level Aggregated] PMCID: PMC5820258
Evidence Type(s): Predictive
Summary: Mutation: p.K601E | Summary: The BRAF p.K601E mutation correlates with response to venetoclax therapy, indicating its potential role in guiding treatment options.
Evidence Type: Predictive Mutation: p.E46K | Summary: The p.E46K mutation in BTG1 is associated with the development of a dominant clone at relapse, suggesting its involvement in resistance to venetoclax treatment.
Evidence Type: Predictive Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with venetoclax resistance, indicating a correlation with treatment response.
Gene→Variant (gene-first): BRAF(673):p.K601E TP53(7157):p.E46K BRAF(673):BRAFV600E
Genes: BRAF(673) TP53(7157)
Variants: p.K601E p.E46K BRAFV600E
In order to assess if oncogenic BRAF signaling may induce venetoclax resistance, we overexpressed mutated BRAF (p.V600E) in a venetoclax-sensitive cell line OCI-LY19 (Fig. 3a). Exome sequencing of this cell line revealed
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic, Functional
Summary: Evidence Type: Predictive | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with venetoclax resistance, indicating a correlation with treatment response. Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development and progression, as evidenced by its role in inducing venetoclax resistance in cell lines. Evidence Type: Functional | Mutation: p.W110 | Summary: The p.W110 mutation in CDKN2A/B is a nonsense mutation that likely alters the molecular function of the gene, contributing to cancer-related processes.
Gene→Variant (gene-first): 673:BRAFV600E 673:p.V600E 7157:p.W110*
Genes: 673 7157
Variants: BRAFV600E p.V600E p.W110*
Finally, case C586 showed a remarkable pattern of convergent evolution (Fig. 2d). We found two SF3B1 mutations (c.1996A > C; p.K666Q and c.1997A > C; p.K666T) affecting the same codon, but evolved in two independent clon
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 14
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: c.1996A > C | Summary: The SF3B1 mutation c.1996A > C was identified in cancer cell subclones that evolved during venetoclax exposure, indicating its contribution to tumor development and progression. Evidence Type: Oncogenic | Mutation: c.1997A > C | Summary: The SF3B1 mutation c.1997A > C was found in subclones that emerged during treatment with venetoclax, suggesting its role in tumor development and progression. Evidence Type: Oncogenic | Mutation: p.K666Q | Summary: The mutation p.K666Q was detected in small subclones before treatment and evolved during venetoclax therapy, indicating its involvement in oncogenic processes. Evidence Type: Oncogenic | Mutation: p.K666T | Summary: The mutation p.K666T was present in subclones that evolved during venetoclax exposure, supporting its role in tumor development and progression.
Gene→Variant (gene-first): 23451:c.1996A > C 23451:c.1997A > C 23451:p.K666Q 23451:p.K666T
Genes: 23451
Variants: c.1996A > C c.1997A > C p.K666Q p.K666T
Patient C548 showed a divergent evolutionary path of two branches (Fig. 2c). One branch (subclone C3 and C4) was selected during venetoclax therapy. This branch harbored a homozygous loss of CDKN2A/B, and mutations in BR
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 13
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: p.K601E | Summary: The mutation p.K601E in BRAF is associated with tumor development and progression, as it was retained in the subclone that emerged during venetoclax therapy. Evidence Type: Oncogenic | Mutation: p.S321fs | Summary: The mutation p.S321fs in MLL3 is implicated in tumor development, as it was present in the subclone that persisted through treatment. Evidence Type: Oncogenic | Mutation: p.Q547fs | Summary: The frameshift deletion p.Q547fs in BIRC3 is recognized as a driver mutation in CLL, contributing to tumorigenesis.
Gene→Variant (gene-first): 673:p.K601E 330:p.Q547fs 58508:p.S321fs
Genes: 673 330 58508
Variants: p.K601E p.Q547fs p.S321fs
To gain insight into the clonal evolution towards therapy resistance, we inferred subclonal populations and reconstructed phylogenetic trees (see Methods). Intriguingly, we observed a wide spectrum of evolutionary dynami
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Summary: Evidence Type: Predictive | Mutation: p.E46K | Summary: The p.E46K mutation in BTG1 is associated with the development of a dominant clone at relapse, suggesting its involvement in resistance to venetoclax treatment. Evidence Type: Oncogenic | Mutation: p.E46K | Summary: The p.E46K mutation contributes to tumor evolution and is selected as a dominant clone, indicating its role in tumor progression. Evidence Type: Oncogenic | Mutation: p.Q36H | Summary: The p.Q36H mutation is part of a branch observed only in the relapse sample, suggesting its contribution to tumor evolution and progression.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
Recurrent genomic changes that evolved during venetoclax treatment were homozygous deletions affecting CDKN2A/B in three patients (C548, C577, C586) and BTG1 missense mutations in two cases (C577: p.Q36H; C789: p.E46K).
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: p.Q36H | Summary: The BTG1 missense mutation p.Q36H may contribute to tumor development or progression in CLL cells under targeted BCL2-inhibition, providing a survival advantage. Evidence Type: Oncogenic | Mutation: p.E46K | Summary: The BTG1 missense mutation p.E46K may contribute to tumor development or progression in CLL cells under targeted BCL2-inhibition, providing a survival advantage.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
In line with previous findings patients responded to venetoclax therapy, even if TP53 was initially mutated in a bi-allelic fashion (5/8 patients). Two patients showed genome alterations that might qualify for further th
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 8
Evidence Type(s): Oncogenic, Predictive
Summary: Evidence Type: Oncogenic | Mutation: p.K601E | Summary: The BRAF p.K601E mutation is described as oncogenic and contributes to tumor development, making it a target for therapies such as MEK inhibitors. Evidence Type: Predictive | Mutation: p.K601E | Summary: The BRAF p.K601E mutation correlates with response to venetoclax therapy, indicating its potential role in guiding treatment options.
Gene→Variant (gene-first): 673:p.K601E
Genes: 673
Variants: p.K601E
Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
[Paper-level Aggregated] PMCID: PMC5820258
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The BRAFV600E mutation was shown to induce venetoclax resistance in a cell line, demonstrating its oncogenic potential in the context of treatment resistance. Functional: The study demonstrates that the overexpression of mutated BRAF (p.V600E) in a cell line resulted in increased venetoclax resistance, highlighting its functional impact on drug sensitivity.
Gene→Variant (gene-first): BRAF(673):BRAFV600E BRAF(673):p.V600E TP53(7157):p.W110* SF3B1(23451):c.1996A > C SF3B1(23451):c.1997A > C SF3B1(23451):p.K666Q SF3B1(23451):p.K666T TP53(7157):p.E46K BTG1(694):p.Q36H BRAF(673):p.K601E BIRC3(330):p.Q547fs KMT2C(58508):p.S321fs
Genes: BRAF(673) TP53(7157) SF3B1(23451) BTG1(694) BIRC3(330) KMT2C(58508)
Variants: BRAFV600E p.V600E p.W110* c.1996A > C c.1997A > C p.K666Q p.K666T p.E46K p.Q36H p.K601E p.Q547fs p.S321fs
In order to assess if oncogenic BRAF signaling may induce venetoclax resistance, we overexpressed mutated BRAF (p.V600E) in a venetoclax-sensitive cell line OCI-LY19 (Fig. 3a). Exome sequencing of this cell line revealed
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the BRAFV600E variant correlates with venetoclax resistance, indicating a relationship between the variant and treatment response. Oncogenic: The passage describes the overexpression of the mutated BRAF (p.V600E) in a cell line, which is associated with increased resistance to venetoclax, suggesting that this somatic variant contributes to tumor progression.
Gene→Variant (gene-first): 673:BRAFV600E 673:p.V600E 7157:p.W110*
Genes: 673 7157
Variants: BRAFV600E p.V600E p.W110*
Finally, case C586 showed a remarkable pattern of convergent evolution (Fig. 2d). We found two SF3B1 mutations (c.1996A > C; p.K666Q and c.1997A > C; p.K666T) affecting the same codon, but evolved in two independent clon
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the SF3B1 mutations in the context of venetoclax exposure and resistance, indicating a correlation between these variants and treatment response. Oncogenic: The SF3B1 mutations are described as evolving during treatment and being selected for during venetoclax therapy, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 23451:c.1996A > C 23451:c.1997A > C 23451:p.K666Q 23451:p.K666T
Genes: 23451
Variants: c.1996A > C c.1997A > C p.K666Q p.K666T
Patient C548 showed a divergent evolutionary path of two branches (Fig. 2c). One branch (subclone C3 and C4) was selected during venetoclax therapy. This branch harbored a homozygous loss of CDKN2A/B, and mutations in BR
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the selection of specific mutations (including p.K601E and p.Q547fs) during venetoclax therapy, indicating a correlation with treatment response. Oncogenic: The mutations p.K601E and p.S321fs are described as contributing to tumor development, as they are retained in the clonal evolution of the cancer during relapse.
Gene→Variant (gene-first): 673:p.K601E 330:p.Q547fs 58508:p.S321fs
Genes: 673 330 58508
Variants: p.K601E p.Q547fs p.S321fs
To gain insight into the clonal evolution towards therapy resistance, we inferred subclonal populations and reconstructed phylogenetic trees (see Methods). Intriguingly, we observed a wide spectrum of evolutionary dynami
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the involvement of BTG1 mutations (p.E46K and p.Q36H) in the resistance to venetoclax treatment, indicating a correlation between these variants and treatment response. Oncogenic: The passage describes the BTG1 mutations as being involved in the clonal evolution towards therapy resistance, suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
Recurrent genomic changes that evolved during venetoclax treatment were homozygous deletions affecting CDKN2A/B in three patients (C548, C577, C586) and BTG1 missense mutations in two cases (C577: p.Q36H; C789: p.E46K).
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how damaging mutations in BTG1, including the p.Q36H and p.E46K variants, may provide a survival advantage to CLL cells under targeted BCL2-inhibition, indicating their contribution to tumor development or progression. Functional: The passage mentions that BTG1 has been shown to counteract cell proliferation, suggesting that the mutations may alter its molecular or biochemical function.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
In line with previous findings patients responded to venetoclax therapy, even if TP53 was initially mutated in a bi-allelic fashion (5/8 patients). Two patients showed genome alterations that might qualify for further th
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 8
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage states that the BRAF (p.K601E) mutation was shown to be oncogenic and can be targeted by MEK inhibitors, indicating its role in tumor development or progression. Predictive: The mention of patients responding to venetoclax therapy, even with the presence of the BRAF mutation, suggests a correlation with treatment response, which aligns with predictive evidence.
Gene→Variant (gene-first): 673:p.K601E
Genes: 673
Variants: p.K601E
In order to assess if oncogenic BRAF signaling may induce venetoclax resistance, we overexpressed mutated BRAF (p.V600E) in a venetoclax-sensitive cell line OCI-LY19 (Fig. 3a). Exome sequencing of this cell line revealed
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the BRAFV600E variant correlates with venetoclax resistance, indicating a relationship between the variant and treatment response. Oncogenic: The passage describes the overexpression of the mutated BRAF (p.V600E) in a cell line, which is associated with increased resistance to venetoclax, suggesting that this somatic variant contributes to tumor progression.
Gene→Variant (gene-first): 673:BRAFV600E 673:p.V600E 7157:p.W110*
Genes: 673 7157
Variants: BRAFV600E p.V600E p.W110*
Finally, case C586 showed a remarkable pattern of convergent evolution (Fig. 2d). We found two SF3B1 mutations (c.1996A > C; p.K666Q and c.1997A > C; p.K666T) affecting the same codon, but evolved in two independent clon
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the SF3B1 mutations in the context of venetoclax exposure and resistance, indicating a correlation between these variants and treatment response. Oncogenic: The SF3B1 mutations are described as evolving during treatment and being selected for during venetoclax therapy, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 23451:c.1996A > C 23451:c.1997A > C 23451:p.K666Q 23451:p.K666T
Genes: 23451
Variants: c.1996A > C c.1997A > C p.K666Q p.K666T
Patient C548 showed a divergent evolutionary path of two branches (Fig. 2c). One branch (subclone C3 and C4) was selected during venetoclax therapy. This branch harbored a homozygous loss of CDKN2A/B, and mutations in BR
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the selection of specific mutations (including p.K601E and p.Q547fs) during venetoclax therapy, indicating a correlation with treatment response. Oncogenic: The mutations p.K601E and p.S321fs are described as contributing to tumor development, as they are retained in the clonal evolution of the cancer during relapse.
Gene→Variant (gene-first): 673:p.K601E 330:p.Q547fs 58508:p.S321fs
Genes: 673 330 58508
Variants: p.K601E p.Q547fs p.S321fs
To gain insight into the clonal evolution towards therapy resistance, we inferred subclonal populations and reconstructed phylogenetic trees (see Methods). Intriguingly, we observed a wide spectrum of evolutionary dynami
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the involvement of BTG1 mutations (p.E46K and p.Q36H) in the resistance to venetoclax treatment, indicating a correlation between these variants and treatment response. Oncogenic: The passage describes the BTG1 mutations as being involved in the clonal evolution towards therapy resistance, suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
Recurrent genomic changes that evolved during venetoclax treatment were homozygous deletions affecting CDKN2A/B in three patients (C548, C577, C586) and BTG1 missense mutations in two cases (C577: p.Q36H; C789: p.E46K).
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how damaging mutations in BTG1, including the p.Q36H and p.E46K variants, may provide a survival advantage to CLL cells under targeted BCL2-inhibition, indicating their contribution to tumor development or progression. Functional: The passage mentions that BTG1 has been shown to counteract cell proliferation, suggesting that the mutations may alter its molecular or biochemical function.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
In line with previous findings patients responded to venetoclax therapy, even if TP53 was initially mutated in a bi-allelic fashion (5/8 patients). Two patients showed genome alterations that might qualify for further th
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 8
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage states that the BRAF (p.K601E) mutation was shown to be oncogenic and can be targeted by MEK inhibitors, indicating its role in tumor development or progression. Predictive: The mention of patients responding to venetoclax therapy, even with the presence of the BRAF mutation, suggests a correlation with treatment response, which aligns with predictive evidence.
Gene→Variant (gene-first): 673:p.K601E
Genes: 673
Variants: p.K601E