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Structure (London, England : 1993) Jun 2024Human mixed lineage leukemia 4 (MLL4), also known as KMT2D, regulates cell type specific transcriptional programs through enhancer activation. Along with the catalytic...
Human mixed lineage leukemia 4 (MLL4), also known as KMT2D, regulates cell type specific transcriptional programs through enhancer activation. Along with the catalytic methyltransferase domain, MLL4 contains seven less characterized plant homeodomain (PHD) fingers. Here, we report that the sixth PHD finger of MLL4 (MLL4) binds to the hydrophobic motif of ten-eleven translocation 3 (TET3), a dioxygenase that converts methylated cytosine into oxidized derivatives. The solution NMR structure of the TET3-MLL4 complex and binding assays show that, like histone H4 tail, TET3 occupies the hydrophobic site of MLL4, and that this interaction is conserved in the seventh PHD finger of homologous MLL3 (MLL3). Analysis of genomic localization of endogenous MLL4 and ectopically expressed TET3 in mouse embryonic stem cells reveals a high degree overlap on active enhancers and suggests a potential functional relationship of MLL4 and TET3.
Topics: Humans; Dioxygenases; Animals; Protein Binding; Mice; DNA-Binding Proteins; Histone-Lysine N-Methyltransferase; Binding Sites; Proto-Oncogene Proteins; Models, Molecular; Myeloid-Lymphoid Leukemia Protein
PubMed: 38579707
DOI: 10.1016/j.str.2024.03.005 -
Pigment Cell & Melanoma Research Sep 2023Mucosal melanoma (MM) is a rare subtype of melanoma with an aggressive clinical course. In cutaneous melanoma (CM), the absence of pigmentation and presence of NRAS/KRAS...
Mucosal melanoma (MM) is a rare subtype of melanoma with an aggressive clinical course. In cutaneous melanoma (CM), the absence of pigmentation and presence of NRAS/KRAS mutations are biomarkers indicating an aggressive clinical course with shorter overall survival. Similar data for MM are missing. We present the real-world outcome data in a cohort of genotyped MM patients and assessed the prognostic relevance of pigmentation- and NRAS/KRAS mutation status. We correlated pathological reports and clinical data with overall survival of patients with MM. Furthermore, we performed clinically integrated molecular genotyping and analyzed real world treatment regimens for covariates associated with clinical outcome. We identified 39 patients with available clinical and molecular data. Patients with amelanotic MM had a significantly shorter overall survival (p = .003). In addition, the presence of a NRAS or KRAS mutation was significantly associated with poor overall survival (NRAS or KRAS p = .024). Currently, it is unknown if the same prognostic relevance for the lack of pigmentation and RAS mutations in CM, exists in MM. Here we analyzed a cohort of MM for outcome measures and determined that two known prognostic biomarkers for CM are in fact novel prognosticators for MM.
Topics: Humans; Melanoma; Skin Neoplasms; Prognosis; Proto-Oncogene Proteins p21(ras); Biomarkers; Mutation; Disease Progression; Proto-Oncogene Proteins B-raf; Melanoma, Cutaneous Malignant
PubMed: 37390098
DOI: 10.1111/pcmr.13104 -
Journal of Thoracic Oncology : Official... Nov 2023
Topics: Humans; Proto-Oncogene Proteins B-raf; Lung Neoplasms
PubMed: 37879765
DOI: 10.1016/j.jtho.2023.08.030 -
Pathologie (Heidelberg, Germany) Sep 2023In recent years, the treatment of colorectal carcinoma has experienced increasing individualization. In addition to RAS and BRAF mutational status that is firmly... (Review)
Review
In recent years, the treatment of colorectal carcinoma has experienced increasing individualization. In addition to RAS and BRAF mutational status that is firmly established in routine diagnostics, new therapeutic options evolved based on MSI and HER2 status as well as primary tumour localization. Offering the best targeted options in therapy requires new evidence-based decision-making algorithms regarding timing and scope of molecular pathological diagnostics in order for patients to receive an optimized therapy according to current treatment guidelines. New targeted therapies, some of which are about to be approved and for which pathology has to provide new molecular pathological biomarkers, will also play an increasingly important role in the future.
Topics: Humans; Colorectal Neoplasms; Proto-Oncogene Proteins B-raf; Pathology, Molecular; Biomarkers
PubMed: 37277480
DOI: 10.1007/s00292-023-01201-9 -
Journal of Cancer Research and Clinical... Aug 2023Tyrosine kinase Fyn is a member of the Src family of kinases. In addition to the wild type, three mRNA splice isoforms of Fyn have been identified; Fyn-B, Fyn-T, and... (Review)
Review
BACKGROUND
Tyrosine kinase Fyn is a member of the Src family of kinases. In addition to the wild type, three mRNA splice isoforms of Fyn have been identified; Fyn-B, Fyn-T, and Fyn-C. Fyn-T is highly expressed in T lymphocytes, and its expression level is significantly higher in mature T cells than in immature T cells. The abnormal expression of Fyn is closely related to the metabolism, proliferation, and migration of tumor cells. Recent studies have shown that Fyn is expressed in a variety of tumor tissues, and its expression and function vary among different tumors. In some tumors, Fyn acts as a pro-oncogene to promote tumor proliferation and metastasis. Moreover, Fyn mutations have been detected in many hematological tumors in recent years, suggesting a critical regulatory role of Fyn in the development of malignancies.
METHODS
This review analyzed the relevant literature in PubMed and other databases.
PURPOSE
The aim of this study was to systemically review recent research findings on various aspects of Fyn in the pathogenesis and treatment of different types of hematological malignancies and suggests possible future research directions for targeted tumor therapy.
CONCLUSION
Fyn could be a novel prognostic marker and therapeutic target. Treatment option targeting Fyn might be beneficial for future studies.
Topics: Humans; Hematologic Neoplasms; Neoplasms; Phosphotransferases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fyn; src-Family Kinases
PubMed: 36754870
DOI: 10.1007/s00432-023-04608-2 -
International Journal of Molecular... Jun 2024The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is... (Review)
Review
The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is usurped by cancer cells to induce and sustain the malignant phenotype. MET stands out as one of the most important oncogenes activated in cancer and its inhibition has been explored since the initial era of cancer-targeted therapy. Different approaches have been developed to hamper MET signaling and/or reduce MET (over)expression as a hallmark of transformation. Considering the great interest gained by cancer immunotherapy, this review evaluates the opportunity of targeting MET within therapeutic approaches based on the exploitation of immune functions, either in those cases where MET impairment is crucial to induce an effective response (i.e., when MET is the driver of the malignancy), or when blocking MET represents a way for potentiating the treatment (i.e., when MET is an adjuvant of tumor fitness).
Topics: Humans; Proto-Oncogene Proteins c-met; Neoplasms; Immunotherapy; Animals; Oncogenes; Molecular Targeted Therapy; Signal Transduction
PubMed: 38892318
DOI: 10.3390/ijms25116109 -
Physiological Research Oct 2023Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas...
Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C.
Topics: Child; Humans; N-Myc Proto-Oncogene Protein; Oncogene Proteins; Nuclear Proteins; Chelating Agents; Neuroblastoma; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Apoptosis; Cell Proliferation
PubMed: 37888971
DOI: 10.33549/physiolres.935184 -
Science (New York, N.Y.) Aug 2023Molecular glues suppress the active form of the oncogenic protein KRAS.
Molecular glues suppress the active form of the oncogenic protein KRAS.
Topics: Humans; Neoplasms; Proto-Oncogene Proteins p21(ras); Cyclophilin A
PubMed: 37590349
DOI: 10.1126/science.adj1001 -
Cancer Discovery Aug 2023Senescent macrophages in the tumor microenvironment support lung tumor initiation and immunosuppression.
Senescent macrophages in the tumor microenvironment support lung tumor initiation and immunosuppression.
Topics: Humans; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Carcinogenesis; Cell Transformation, Neoplastic; Lung; Macrophages; Tumor Microenvironment
PubMed: 37326376
DOI: 10.1158/2159-8290.CD-RW2023-092 -
Cell Reports Aug 2023MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc mice are...
MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. "MycKO" mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.
Topics: Humans; Mice; Animals; Aging, Premature; Proto-Oncogene Proteins c-myc; Incidence; Neoplasms; Aging
PubMed: 37481724
DOI: 10.1016/j.celrep.2023.112830