This case underscores the potential for eosinophilia to occur prior to tumor development, challenging the current understanding of the relationship between eosinophilia and cancer. Further research is warranted to explore the implications of eosinophilia in cancer pathogenesis and its clinical significance.

2 days ago

Journal • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • NOTCH1 (Notch 1) • NOTCH2 (Notch 2)

PD-L1 expression • NOTCH1 mutation

12d

Primary Endpoint Evaluation of a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease (ASH 2024)

Responses are durable, with 89%, 87%, and 77% 4-yr PFS in all-comer, uIGHV, and TP53 aberrant pts. Our data support further study of AVO for pts with TN high risk CLL in GCLLSG CLL16 and future trials.

12 days ago

Clinical • P2 data • IO biomarker

TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • IGH (Immunoglobulin Heavy Locus)

TP53 mutation • NOTCH1 mutation

clonoSEQ

Venclexta (venetoclax) • Gazyva (obinutuzumab) • Calquence (acalabrutinib)

24d

Personalized Treatment Strategies via Integration of Gene Expression Biomarkers in Molecular Profiling of Laryngeal Cancer. (PubMed, J Pers Med)

This review seeks to provide a comprehensive framework for promoting personalized cancer therapy by combining the most recent data on gene expression profiling in laryngeal cancer. Molecularly guided treatment options may enhance patient outcomes.

24 days ago

Review • Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • CD44 (CD44 Molecule) • ALDH1A1 (Aldehyde Dehydrogenase 1 Family Member A1)

PIK3CA mutation • NOTCH1 mutation • CD44 expression

2ms

MicroRNA Profiling as a Predictive Indicator for Time to First Treatment in Chronic Lymphocytic Leukemia: Insights from the O-CLL1 Prospective Study. (PubMed, Noncoding RNA)

In conclusion, the identification of specific miRNAs as predictors of TTFT holds promise for enhancing risk stratification in CLL to predict therapeutic needs. However, further validation studies and in-depth functional analyses are required to confirm the robustness of these observations and to facilitate their translation into meaningful clinical utility.

2 months ago

Journal

NOTCH1 (Notch 1) • B2M (Beta-2-microglobulin) • MIR625 (MicroRNA 625) • MIR99A (MicroRNA 99a) • MIR148A (MicroRNA 148a) • MIR150 (MicroRNA 150) • MIR193A (MicroRNA 193a) • MIR33A (MicroRNA 33a) • MIR582 (MicroRNA 582) • MIR671 (MicroRNA 671) • MIR124-3 (MicroRNA 124-3)

NOTCH1 mutation • Chr del(11q)

2ms

Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (clinicaltrials.gov)

P2, N=15, Active, not recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial completion date: Dec 2026 --> Dec 2025

2 months ago

Trial completion date • IO biomarker

TP53 (Tumor protein P53) • SF3B1 (Splicing Factor 3b Subunit 1)

TP53 mutation • NOTCH1 mutation • SF3B1 mutation

Keytruda (pembrolizumab) • Imbruvica (ibrutinib) • fludarabine IV

3ms

Molecular characterization of metastatic penile squamous cell carcinoma in developing countries and its impact on clinical outcomes: LACOG 2018 translational study. (PubMed, Oncologist)

This study demonstrated that molecular alterations in mPSCC from developing countries are similar to those from developed countries. Predictive biomarkers for immunotherapy response such as TMB high or MSI were not identified. Specific gene mutations may identify patients with worse prognoses and open new avenues for therapeutic development.

3 months ago

Clinical data • Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases

PD-L1 expression • NOTCH1 mutation • CDKN2B deletion

6ms

Unveiling the dynamics and molecular landscape of a rare chronic lymphocytic leukemia subpopulation driving refractoriness: insights from single-cell RNA sequencing. (PubMed, Mol Oncol)

In addition, we successfully tracked the cells with high genomic complexity back to the time before treatment, where they formed a rare subpopulation. We have confirmed that single-cell RNA sequencing enables the characterization of refractory cells and the monitoring of their development over time.

6 months ago

Journal

CD20 (Membrane Spanning 4-Domains A1) • NOTCH1 (Notch 1) • PAX5 (Paired Box 5) • CD79A (CD79a Molecule) • MS4A1 (Membrane Spanning 4-Domains A1)

NOTCH1 mutation

6ms

Role of Mutation of NOTCH1 gene in development of oral squamous cell carcinoma: a narrative review. (PubMed, J Pak Med Assoc)

Once activated, the pathway is involved in tumour progression and metastasis. The Asians compared to Caucasians are more affected by neurogenic locus notch homolog protein 1 mutations.

6 months ago

Review • Journal

NOTCH1 (Notch 1) • EGF (Epidermal growth factor)

NOTCH1 mutation

6ms

COMBINED PIRTOBRUTINIB, VENETOCLAX, AND OBINUTUZUMAB IN FIRST-LINE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A PHASE 2 TRIAL (EHA 2024)

Background: Treatment with combined covalent BTK-inhibitor (cBTKi such as ibrutinib, acalabrutinib, zanubrutinib) withBCL2-inhibitor, venetoclax +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectableMRD (U-MRD) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report the first results for first-line combined pirtobrutinib, venetoclax, and obinutuzumab in pts with CLL. Avery high rate of bone marrow U-MRD at 10-6 sensitivity was noted at 6-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents.

6 months ago

P2 data • Clinical

TP53 (Tumor protein P53)

TP53 mutation • KRAS mutation • NOTCH1 mutation • Chr del(11q) • SF3B1 mutation • TP53 mutation + Chr del(17p) • Chr del(17p) + Chr del(11q) • TS 12

clonoSEQ

Venclexta (venetoclax) • Imbruvica (ibrutinib) • Gazyva (obinutuzumab) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Jaypirca (pirtobrutinib)

7ms

Biofunctional study on chemoresistance in esophageal squamous carcinoma cells induced by missense mutation of NOTCH1 p.E450K. (PubMed, J Thorac Dis)

The NOTCH1 p.E450K point mutation causes chemotherapy resistance in KYSE140 and KYSE450 ESCC cells. Cell functional experiments showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, migration and invasion abilities of KYSE140 and KYSE450 cells and increased the number of cells in S phase.

7 months ago

Journal

NOTCH1 (Notch 1)

NOTCH1 mutation

7ms

Molecular characteristics and multivariate survival analysis of 43 patients with locally advanced or metastatic esophageal squamous cell carcinoma. (PubMed, J Thorac Dis)

NOTCH1, CBLB and TSC2 alterations were found to be potential indicators of poor prognosis in patients with ESCC. TMB was also positively correlated with the OS of ESCC patients, providing valuable insights for their treatment strategies.

7 months ago

Journal • Tumor mutational burden • Metastases

TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • CCND1 (Cyclin D1) • FGF19 (Fibroblast growth factor 19) • TSC2 (TSC complex subunit 2)

TP53 mutation • NOTCH1 mutation • CDKN2A mutation • TSC2 mutation

8ms

Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma. (PubMed, Cancer Cell)

Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

8 months ago

Journal

NOTCH1 (Notch 1)

NOTCH1 mutation

Tibsovo (ivosidenib) • Voranigo (vorasidenib)

8ms

Notch signaling genes and CD8+ T-cell dynamics: Their contribution to immune-checkpoint inhibitor therapy in oral squamous cell carcinoma: A retrospective study. (PubMed, Cancer Med)

Four of 10 patients were positive for PD-L1 and CD8+ T. By analyzing WES in three of these four patients, we notably identified the mutations of NOTCH1, FBXW7, and noncoding RNA intronic mutation in NOTCH2NLR in two of these three patients. This study may enable better selection of ICI therapy with CD8+ T-cell infiltration via PD-L1 expression for oral squamous cell carcinoma patients with mutations in Notch signaling pathway.

8 months ago

Retrospective data • Journal • Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • NOTCH1 (Notch 1) • CD8 (cluster of differentiation 8) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

PD-L1 expression • NOTCH1 mutation • NOTCH2 mutation • NOTCH mutation

8ms

Integrated analysis of transcriptome and genome variations in pediatric T cell acute lymphoblastic leukemia: data from north Indian tertiary care center. (PubMed, BMC Cancer)

Overall, the present study demonstrates the frequencies of transcriptomic and genetic alterations from Indian cohort of pediatric T-ALL and is a salient addition to current genomics data sets available in T-ALL.

8 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • ABL1 (ABL proto-oncogene 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • JAK2 (Janus kinase 2) • MTAP (Methylthioadenosine Phosphorylase) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • ETV6 (ETS Variant Transcription Factor 6) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • JAK3 (Janus Kinase 3) • PHF6 (PHD Finger Protein 6) • SPI1 (Spi-1 Proto-Oncogene) • LPAR6 (Lysophosphatidic Acid Receptor 6) • NKX3-1 (NK3 homeobox 1) • RAG1 (Recombination Activating 1) • TCF7 (Transcription Factor 7)

KRAS mutation • NOTCH1 mutation • CDKN2A deletion • JAK3 mutation • KRAS deletion

9ms

Feasibility and clinical utility of blood based NGS in head and neck carcinomas : A single center experience from precision medicine program. (AACR 2024)

This study demonstrates the feasibility of liquid biopsy in HNSCC and rare head and neck tumors, providing valuable therapeutic and prognostic insights. The findings underscore the potential of liquid biopsy as a valuable tool in clinical decision-making for head and neck cancer patients.

9 months ago

Clinical • Next-generation sequencing

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • DNMT3A (DNA methyltransferase 1) • NOTCH1 (Notch 1) • ASXL1 (ASXL Transcriptional Regulator 1) • FGF19 (Fibroblast growth factor 19) • FGF3 (Fibroblast growth factor 3) • CHEK2 (Checkpoint kinase 2) • STING (stimulator of interferon response cGAMP interactor 1)

TP53 mutation • PIK3CA mutation • NOTCH1 mutation • FGF3 amplification

FoundationOne® Liquid CDx

9ms

Renin-Angiotensin System Inhibitors Suppress the Growth of Leukemia Cells. (PubMed, Anticancer Res)

RAS inhibitors can be repurposed as molecular-targeted drugs for leukemia. However, the concentrations of the inhibitors were much higher than those in the plasma of patients with hypertension. Therefore, further investigation is required for their clinical use.

9 months ago

Journal • PARP Biomarker

MYC (V-myc avian myelocytomatosis viral oncogene homolog) • NOTCH1 (Notch 1) • CASP3 (Caspase 3)

NOTCH1 mutation • MYC expression

captopril

9ms

Effect of Ferroptosis Inducers and Inhibitors on Cell Proliferation in Acute Leukemia. (PubMed, Anticancer Res)

Ferroptosis inducers may serve as potential candidates for novel molecular therapy against AML and T-ALL.

9 months ago

Journal

MYC (V-myc avian myelocytomatosis viral oncogene homolog) • NOTCH1 (Notch 1) • GPX4 (Glutathione Peroxidase 4) • CCND3 (Cyclin D3)

NOTCH1 mutation • MYC expression • NOTCH1 expression

erastin • RSL3

9ms

Thymic-Epithelial-Cell-Dependent Microenvironment Influences Proliferation and Apoptosis of Leukemic Cells. (PubMed, Int J Mol Sci)

In support, we also detected metabolic changes as potential drivers of leukemic cell survival. Our studies could shed light on T-cell/stroma crosstalk to human leukemic cells and propose our culture system to test pharmacological treatment for T-ALL.

9 months ago

Journal

NOTCH1 (Notch 1) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • NOTCH3 (Notch Receptor 3) • CXCL12 (C-X-C Motif Chemokine Ligand 12)

NOTCH1 mutation • NOTCH3 mutation • NOTCH3 overexpression

10ms

Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders. (PubMed, J Clin Exp Hematop)

The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary.

10 months ago

Journal

CD20 (Membrane Spanning 4-Domains A1) • NOTCH1 (Notch 1)

CD20 positive • NOTCH1 mutation • NOTCH1 expression

methotrexate

10ms

CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders. (PubMed, Int J Mol Sci)

Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

10 months ago

Journal

NOTCH1 (Notch 1)

NOTCH1 mutation

Venclexta (venetoclax) • Imbruvica (ibrutinib)

10ms

NOTCH1-Induced T-Cell Acute Lymphoblastic Leukemia In Vivo Models. (PubMed, Methods Mol Biol)

The protocol presented here describes a method for in vivo T-ALL transformation driven by the retroviral transduction of hematopoietic progenitors with oncogenic mutant forms NOTCH1 and subsequent transplant into recipient mice. This T-ALL transformation model allows the interaction between the leukemia cells and the bone marrow microenvironment, better recapitulating the physiological conditions that promote the development of the human disease, providing a versatile tool for both experimental therapeutics and functional genetics studies on T-ALL.

10 months ago

Preclinical • Journal

NOTCH1 (Notch 1)

NOTCH1 mutation

10ms

IMMUNOPHENOTYPE OF LEUKEMIC CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS WITH NOTCH1 AND SF3B1 GENE MUTATIONS. (PubMed, Exp Oncol)

Our data confirmed a reduced CD20 expression in CLL patients with NOTCH1 and SF3B1 mutations. In addition, an approach was proposed to identify high-risk CLL patients for prediction of such mutations: previously untreated CLL patients at advanced Binet - Rai stages (BII, CIII, CIV) with a reduced number of double-positive CD20+CD5+ cells in peripheral blood and/or low iMFI of CD20+ cells.

10 months ago

Journal

TP53 (Tumor protein P53) • CD20 (Membrane Spanning 4-Domains A1) • NOTCH1 (Notch 1) • SF3B1 (Splicing Factor 3b Subunit 1) • CD5 (CD5 Molecule)

TP53 mutation • NOTCH1 mutation • SF3B1 mutation • CD20 expression • NOTCH1 expression

10ms

Clinical and molecular biological characterization of patients with accelerated chronic lymphocytic leukemia (PubMed, Zhonghua Xue Ye Xue Za Zhi)

Patients with aCLL exhibited a clinically aggressive course, often accompanied by unfavorable prognostic factors, including unmutated IGHV, +12, ATM mutation, and NOTCH1 mutation. Patients with CLL/SLL with clinical suspicion of disease progression, especially those with bulky disease and PET-CT SUVmax ≥5, should undergo biopsy at the site of highest metabolic uptake to establish a definitive pathological diagnosis.

10 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • ATM (ATM serine/threonine kinase) • NOTCH1 (Notch 1) • IGH (Immunoglobulin Heavy Locus)

KRAS mutation • ATM mutation • NOTCH1 mutation

11ms

Molecular characterization of metastatic penile carcinoma (mPC) in developing countries and its association with clinical outcomes: LACOG 2018 FOUNDATION translational trial. (ASCO-GU 2024)

This translational study demonstrated that molecular alterations in mPC in developing countries are similar to those in patients from developed countries. Predictive biomarkers for immunotherapy, such as TMB high or MSI, were not identified in this study cohort. Specific gene mutations may identify patients with worse prognoses and open new avenues for therapeutic development.

11 months ago

Clinical data • Clinical • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases

PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)

PD-L1 expression • TMB-L • NOTCH1 mutation • CDKN2B deletion

FoundationOne® CDx

11ms

NOTCH1 Mutations Predict Superior Outcomes of Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. (PubMed, Immunotargets Ther)

NOTCH1-mutant tumors displayed an inflamed tumor microenvironment (TME), manifesting as increased PD-L1 expression and tumor-infiltrating CD8+ T cells. NOTCH1 mutations define a molecular subtype of NSCLC, which are more common in smokers and patients with SCC, are characterized with higher TMB, inflamed TME, and display improved survival of ICB therapy for NSCLC patients.

11 months ago

Checkpoint inhibition • Journal • PD(L)-1 Biomarker • IO biomarker • Checkpoint block

PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • NOTCH1 (Notch 1) • CD8 (cluster of differentiation 8)

PD-L1 expression • TMB-H • NOTCH1 mutation

MSK-IMPACT

11ms

Recurrent mutations in Refractory/Relapsed Diffuse Large B cell Lymphoma by targeted gene sequencing. (PubMed, Cytogenet Genome Res)

Co-occurrence of loss of function mutations of TNFAIP3 and missense mutations in MYD88 was associated with a non-responsive cohort. Discussion-The study highlights mutations associated with chemotherapeutic response in DLBCL with implications for initial diagnostic biopsy response prediction.

11 months ago

Journal

TP53 (Tumor protein P53) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • TNFAIP3 (TNF Alpha Induced Protein 3) • CD58 (CD58 Molecule)

TP53 mutation • NOTCH1 mutation • MYD88 mutation • EZH2 mutation

12ms

Exploring the molecular features and genetic prognostic factors of pulmonary high-grade neuroendocrine carcinomas. (PubMed, Hum Pathol)

IHC for Rb was reliable for predicting LCNEC molecular subtypes, indicating its clinical value. NCOR2 and SPTA1 alterations were identified as prognostic factors that may provide therapeutic targets for patients with NEC.

12 months ago

Journal

EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53) • RB1 (RB Transcriptional Corepressor 1) • NOTCH1 (Notch 1) • KMT2D (Lysine Methyltransferase 2D) • LRP1B (LDL Receptor Related Protein 1B) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • FAT3 (FAT Atypical Cadherin 3) • NCOR2 (Nuclear Receptor Corepressor 2) • SPTA1 (Spectrin Alpha) • AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1) • SFTPA1 (Surfactant Protein A1)

TP53 mutation • EGFR mutation • NOTCH1 mutation • KMT2D mutation • HIF1A expression

12ms

Prostate Cancer Patient Stratification by Molecular Signatures in the Veterans Precision Oncology Data Commons. (PubMed, Cold Spring Harb Mol Case Stud)

Hierarchical clustering analysis revealed two subgroups containing therapeutically targetable molecular features with novel mutational signatures distinct from those reported in the Catalogue of Somatic Mutations in Cancer database. The clustering approach presented in this study can potentially be used to clinically stratify patients based on their distinct mutational profiles and identify actionable somatic mutations for precision oncology.

12 months ago

Journal • Tumor mutational burden

TMB (Tumor Mutational Burden) • ABL1 (ABL proto-oncogene 1) • PTEN (Phosphatase and tensin homolog) • NOTCH1 (Notch 1) • KMT2A (Lysine Methyltransferase 2A) • MSH6 (MutS homolog 6) • SMO (Smoothened Frizzled Class Receptor)

PTEN mutation • NOTCH1 mutation • VHL mutation • SMO mutation

12ms

Comprehensive analysis of the proximity-dependent nuclear interactome for the oncoprotein NOTCH1 in live cells. (PubMed, J Biol Chem)

Through data mining, we also revealed potential drug targets for the inhibition of Notch signaling. Collectively, these results provide a valuable resource to uncover the mechanisms that fine-tune Notch signaling in tumorigenesis and inform therapeutic targets for Notch-addicted tumors.

12 months ago

Journal

NOTCH1 (Notch 1) • HDAC1 (Histone Deacetylase 1) • NICD (NOTCH1 intracellular domain) • USP7 (Ubiquitin Specific Peptidase 7)

NOTCH1 mutation

12ms

High Deletion Burden Identified By Whole Genome Sequencing Is Associated with Enhanced Risk in del17p CLL Patients (ASH 2023)

Using genome wide sequencing, we identify increasing genomic deletions as a feature of enhanced-high risk del17p. While deletion burden cut-offs identified here are specific to our research method and require further validation in additional independent cohorts, EHR subgroup remained significant after adjusting for other known prognostic variables .

12 months ago

Clinical • Whole genome sequencing

TP53 (Tumor protein P53) • NOTCH1 (Notch 1) • IGH (Immunoglobulin Heavy Locus) • CHD2 (Chromodomain Helicase DNA Binding Protein 2)

TP53 mutation • ATM mutation • NOTCH1 mutation • Chr del(11q) • IGH mutation • TS 12

12ms

A New t(7; 9)(p12; q34) Involving NOTCH1 and IKZF1 in Pediatric T-Cell Lymphoblastic Lymphoma (ASH 2023)

Summary/perspectivesThis new t(7; 9)(p12; q34) involving ICN1 illustrates the importance to look for ICN1 more extensively in parallel to NOTCH1/FBXW7 mutations in the screening of Notch1 activation pathway in T-ALL/LL specially in the event of a stratification on Notch1 status for treatment. As both NOTCH1 and IKZF1 are major actors of normal T-cell differentiation/proliferation, the oncogenic role of the fusion NOTCH1: : IKZF1 in T-ALL/LL deserves a better understanding in a larger population and will be further explored.

12 months ago

Clinical

NOTCH1 (Notch 1) • CD8 (cluster of differentiation 8) • IKZF1 (IKAROS Family Zinc Finger 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • CD4 (CD4 Molecule) • CD7 (CD7 Molecule)

NOTCH1 mutation • FBXW7 mutation

12ms

Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis. (PubMed, Leukemia)

Both myeloid and T-cell leukemias engrafted in immunocompromised hosts. These data underline the potential of Xenopus tropicalis for modeling human leukemia, where mosaic gene disruption, combined with deep amplicon sequencing of the targeted genomic regions, can rapidly and efficiently expose co-operating driver gene mutations.

12 months ago

Journal • Epigenetic controller

NOTCH1 (Notch 1) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

NOTCH1 mutation • EZH2 mutation

12ms

Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (clinicaltrials.gov)

P2, N=15, Active, not recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial completion date: Dec 2030 --> Dec 2026

12 months ago

Trial completion date

TP53 (Tumor protein P53) • SF3B1 (Splicing Factor 3b Subunit 1)

TP53 mutation • NOTCH1 mutation • SF3B1 mutation

Keytruda (pembrolizumab) • Imbruvica (ibrutinib) • fludarabine IV

1year

NOTCH1 and PIK3CA mutation are related to HPV-associated vulvar squamous cell carcinoma. (PubMed, Pathol Res Pract)

In contrast, PIK3CA mutations favored hotspot codons 1624 and 1633 of the gene, indicating that PIK3CA acts as an oncogene in vulvar carcinogenesis. In conclusion, NOTCH1 and PIK3CA mutations are detectable in a substantial proportion of vulvSCC and are related to HPV infection and more aggressive tumor behaviour.

1 year ago

Journal

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NOTCH1 (Notch 1) • EGF (Epidermal growth factor)

PIK3CA mutation • NOTCH1 mutation

1year

IDH mutant astrocytomas without receiving adjuvant treatment do not develop hypermutation or specific gene mutation and MYC, CDKN2A and PDGFRA are involved in malignant transformation (SNO 2023)

IDH-mutant low grade astrocytomas not being treated with temozolomide or irradiation do not develop hypermutation or specific gene mutation for their natural evolution and malignant transformation.

1 year ago

Clinical

TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NOTCH1 (Notch 1) • POLE (DNA Polymerase Epsilon) • ATRX (ATRX Chromatin Remodeler)

TP53 mutation • POLE mutation • NOTCH1 mutation • CDKN2A deletion • CDKN2A mutation • ATRX mutation • PDGFRA mutation

temozolomide

1year

Frontline Consolidation with Nelarabine for Adults with High-Risk T-Cell Acute Lymphoblastic Leukemia. Results of the Graall-2014/T Atriall Phase 2 Study (ASH 2023)

NELA was given at 1,500 mg/sqm/day at day 1,3 and 5 in combination with etoposide and cyclophosphamide for a maximum of 5 courses during consolidation (2 cycles) and maintenance (3 cycles). While NELA did not yield an overall improved outcome in the study population, benefits were observed in favorable MRD responders and non-ETP patients. Additional prospective studies are needed to further delineate the specific patient subgroups that might benefit from NELA.

1 year ago

Clinical • P2 data

PTEN (Phosphatase and tensin homolog) • NOTCH1 (Notch 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

PTEN mutation • NOTCH1 mutation • FBXW7 mutation

cyclophosphamide • etoposide IV • nelarabine

1year

Extended Follow-up and Resistance Mutations in CLL Patients Treated with Acalabrutinib (ASH 2023)

Understanding of acquired resistance to cBTKi therapy has largely come from data on patients (pts) treated with the first-in-class cBTKi ibrutinib...In contrast, much less is known about genetic mechanisms of drug resistance in pts treated with next generation cBTKi acalabrutinib and zanubrutinib... After a median follow-up of 6.5 years (IQR 2.9-6.3), 23/48 (48%) pts developed PD (20 CLL, 3 RT). PD occurred in 17/32 (53%) R/R pts and 6/16 (38%) TN pts. Median progression-free survival was reached at 6.0 years.

1 year ago

Clinical

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NOTCH1 (Notch 1) • SF3B1 (Splicing Factor 3b Subunit 1) • KMT2D (Lysine Methyltransferase 2D) • CREBBP (CREB binding protein) • BIRC3 (Baculoviral IAP repeat containing 3) • PLCG2 (Phospholipase C Gamma 2) • NFKBIE (NFKB Inhibitor Epsilon)

TP53 mutation • BRAF mutation • ATM mutation • NOTCH1 mutation • SF3B1 mutation • PLCG2 mutation • BTK mutation • BTK C481 • BTK T474I

Imbruvica (ibrutinib) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib)

1year

ZMYM3 Mutations Cooperate with NOTCH1 Alterations, Reduce Histone H4 Acetylation and Promote Apoptosis Evasion in Chronic Lymphocytic Leukemia (ASH 2023)

Mutations in ZMYM3 are mainly loss-of-function, associate with NOTCH1 signaling mutations and shorten TFT in CLL patients, suggesting that ZMYM3 mutational status may be a useful marker in the management of early stage CLL patients. Moreover, ZMYM3 mutations reduce histone H4 acetylation and cooperate with NOTCH1 mutations to dysregulate gene-expression, leading to impair DNA damage response and apoptosis evasion.

1 year ago

BRCA Biomarker • IO biomarker • Epigenetic controller

BRCA1 (Breast cancer 1, early onset) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • RAD51 (RAD51 Homolog A) • CASP8 (Caspase 8) • ZMYM3 (Zinc Finger MYM-Type Containing 3)

NOTCH1 mutation • NOTCH mutation • ZMYM3 mutation

1year

A Phase 2 Study of Acalabrutinib, Umbralisib, and Ublituximab (AU2) in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (ASH 2023)

Immune-related adverse events were frequently observed and required dose reduction of umbralisib in 38% of the patients but most were then able to stay on therapy. Longer follow-up is required to determine durability of remission off therapy.

1 year ago

P2 data • IO biomarker

TP53 (Tumor protein P53) • ATM (ATM serine/threonine kinase) • NOTCH1 (Notch 1) • SF3B1 (Splicing Factor 3b Subunit 1) • IGH (Immunoglobulin Heavy Locus) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)

TP53 mutation • ATM mutation • NOTCH1 mutation • SF3B1 mutation • ATM deletion • TS 12

Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)