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BIOMARKER:

BCL2 mutation

i
Other names: BCL2, Bcl-2, PPP1R50, B-cell CLL/lymphoma 2
Entrez ID:
3ms
Viability of ROR1-high primary CLL cells cultured in serum-free media, with or without cirmtuzumab (20 μg/mL) with or without exogenous Wnt5a (200 ng/mL) and with venetoclax at concentrations ranging from 0.5nM to 4nM, was determined at 16h. Conclusion Collectively, these studies indicate that expression of ROR1 can enhance cancer-stemness and venetoclax resistance. Because the resistance of CLL cells to venetoclax can be enhanced by WNT5a-induced ROR1 signaling, strategies targeting ROR1 may enhance the efficacy of venetoclax-based regimens and/or mitigate the risk of developing PD on venetoclax therapy.
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • IGH (Immunoglobulin Heavy Locus) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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IGH mutation • BCL2 expression • BCL2 mutation • ROR1 expression
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Venclexta (venetoclax) • cirmtuzumab (UC-961)
3ms
Venetoclax (VEN) plus azacitidine has become the first-line therapy for elderly patients with acute myeloid leukemia (AML), and has a complete remission (CR) plus CR with incomplete recovery of hemogram rate of ≥70%. Instead, we found that reconstructed existing mutations, especially dominant mutation conversion (e.g., expanded FLT3-ITD), rather than newly emerged mutations (e.g., TP53 mutation), mainly contributed to VEN resistance in AML. According to our results, the combination of precise mutational monitoring and advanced interventions with targeted therapy or chemotherapy are potential strategies to prevent and even overcome acquired VEN resistance in AML.
Journal • IO biomarker
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2)
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TP53 mutation • FLT3-ITD mutation • BCL2 mutation
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Venclexta (venetoclax) • azacitidine
3ms
This study demonstrated that, in patients treated with R-CHOP, the presence of BCL2 alteration, especially BCL2GA/AMP, and TP53 mutation were significantly associated with inferior outcomes independent of IPI . The novel prognostic models we proposed could aid in individual risk prediction for DLBCL patients treated with R-CHOP . Further validation of this prognostic model is warranted.
IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
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TP53 mutation • BCL2 mutation • BCL2 amplification • BCL2 translocation
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Rituxan (rituximab)
3ms
Although most commonly observed in heavily pre-treated patients with disease refractory to fludarabine and harboring complex karyotype (CK), Richter transformation (RT) presents a distinct and challenging manifestation of venetoclax resistance. However, data to inform clinical decisions for these patients are limited. We review the biology of venetoclax resistance and outline an approach to the common clinical scenarios encountered after venetoclax-based therapy that will increasingly confront practising clinicians.
Journal • IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2)
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BCL2 mutation
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Venclexta (venetoclax) • fludarabine IV
5ms
Collectively these studies demonstrate that Wnt5a-induced ROR1-signaling in CLL promotes cancer dedifferentiation/stemness and increases resistance to Ven. Strategies that inhibit ROR1-signaling with agents such as cirmtuzumab may enhance the cytotoxic activity of venetoclax and/or mitigate risk of developing resistance to venetoclax therapy.
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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BCL2 mutation • ROR1 expression
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Venclexta (venetoclax) • cirmtuzumab (UC-961)
5ms
Strong and persistent tumor regression in xenograft models of lymphoid malignancies in mouse and rat were observed at well tolerated doses following weekly IV administration of S65487 in combination with the MCL-1-specific inhibitor, S64315/MIK665. Altogether, these data demonstrate that S65487/VOB560 has significant therapeutic potential against human lymphoid and myeloid malignancies as well as in patients with Venetoclax resistant leukemias. Clinical studies are currently ongoing with S65487/VOB560 (NCT03755154).
Clinical • IO biomarker
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BCL2L1 (BCL2-like 1)
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BCL2 mutation • BCL2 G101V
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Venclexta (venetoclax) • Bcl-2 Family Inhibitors • MIK665 • S65487
9ms
Ex vivo drug treatments included: BCL2i (inhibitor): venetoclax; MCL-1i: AZD5991, S63845 and BCLXLi: A133...No mutations in EZH2, CREBBP or EP300 were found... The genomic landscape of BCL2-R CLL is characterized by a high frequency of trisomy 12, subclonal NOTCH and RAS pathway mutations, as well as BCL2 and MLL2 mutations. Protein expression, BH3 profiling and viability assays data are consistent with nearly exclusive dependence on Bcl-2. Our data suggest that Bcl-2 inhibition should be favored over Mcl-1 inhibition in BCL2-R CLL.
IO biomarker
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BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • SF3B1 (Splicing Factor 3b Subunit 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • KMT2D (Lysine Methyltransferase 2D) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • BCL2L1 (BCL2-like 1) • BIRC3 (Baculoviral IAP repeat containing 3) • CREBBP (CREB binding protein) • EP300 (E1A binding protein p300) • BCL2L11 (BCL2 Like 11) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2)
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TP53 mutation • BRAF mutation • NOTCH1 mutation • KMT2D mutation • MYD88 L265P • EZH2 mutation • MCL1 expression • BCL2 mutation • BCL2 rearrangement • BCL2 G101V
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Venclexta (venetoclax) • S63845 • AZD5991 • EP-300
9ms
Introduction Progression of disease within 2 years after starting rituximab-chemotherapy (POD24) has been identified as a convincing adverse prognostic factor for follicular lymphoma (FL), and can serve as a clinical endpoint to identify patients at high risk of early lymphoma-related mortality...We performed CAPP-seq to detect the mutation status of the genes included in m7-FLIPI and POD24 PI (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), as well as BCL2, TNFRSF14 and TP53...Though retaining their prognostic value, the integration of mutations onto the clinical biomarker-based prognostic scores has a limited discrimination capacity for POD24. Our results prompt the investigation of: i) POD discrimination capacity of prognostic models based on molecular phenotypes (i.e. gene expression) reflecting the tumor-microenvironment milieu; ii) new models based on a combination of biomarkers capturing the most informative clinical, genetic and phenotypic features.
Clinical • IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • ARID1A (AT-rich interaction domain 1A) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • CREBBP (CREB binding protein) • CARD11 (Caspase Recruitment Domain Family Member 11) • EP300 (E1A binding protein p300) • FOXO1 (Forkhead box O1)
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TP53 mutation • EZH2 mutation • BCL2 mutation • EZH2 positive
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Rituxan (rituximab) • EP-300
9ms
Plasma cfDNA genotyping may be useful for improving diagnosis and prognosis especially in symptomatic FL patients. Given that some somatic mutations associated with disease progression are detected only in plasma cfDNA samples, cfDNA genotyping may be useful for choosing appropriate therapy for high-risk FL patients.
Clinical • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • KMT2D (Lysine Methyltransferase 2D) • CREBBP (CREB binding protein) • B2M (Beta-2-microglobulin) • CARD11 (Caspase Recruitment Domain Family Member 11) • CCND3 (Cyclin D3) • STAT6 (Signal transducer and activator of transcription 6)
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LDH elevation • BCL2 mutation
9ms
Ninety-seven percent of the BCL2 mutations occurred within G4 sites that overlapped with AID binding. G4 localization at sites of mutation, and within aggressive DLBCL tumors harboring amplified BCL2 and MYC, supports a role for G4 structures in events that lead to a loss of genomic integrity, a critical step in B-cell lymphomagenesis.
Journal
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BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)
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BCL2 mutation
10ms
Journal
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BCL2 (B-cell CLL/lymphoma 2)
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BCL2 mutation
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Venclexta (venetoclax)