Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a family with a dominantly transmitted syndrome resembling Fanconi's anemia and spanning two generations. This syndrome was characterized by an ill-defined hematologic stem cell disorder, immune dysfunction, poor dentition, hyperpigmented skin, warts, and multiple second trimester spontaneous abortions and included one case of acute myelomonocytic leukemia (acute non-lymphocytic leukemia, M4). This family lacks the characteristic chromosomal aberrations of Fanconi's anemia. We believe this constellation of findings represents an entity not previously described.
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PMID:Dominantly transmitted hematologic dysfunction clinically similar to Fanconi's anemia. 281 20

Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) was performed in skin from patients with various malignant and nonmalignant skin diseases using anti-PCNA monoclonal antibodies. The malignant diseases included squamous cell carcinoma (SCC), adult T lymphotrophic leukemia (ATL), mycosis fungoides, malignant melanoma and malignant lymphoma, and the nonmalignant diseases included severe treatment-resistant atopic dermatitis (AD), psoriasis vulgaris, verruca vulgaris, and others. The percentage of PCNA-positive cells (the labeling index, LI) was highest for the malignant diseases (56.5+/-7.1%). The LIs for severe treatment-resistant AD, psoriasis, and verruca vulgaris were also significantly higher than those for the normal control or nonlesional skin of the patients. The PCNA LIs were, however, not significantly elevated in eczema and contact dermatitis. The high PCNA LIs in severe AD and psoriasis vulgaris were considerably lower in the skin improved by treatment. Labeling with Ki67, a nuclear protein expressed in cycling cells, was also performed in skin from subsets of each patient group. The results were very similar to those found with PCNA labeling. PCNA-positive cells were found throughout the dermis as well as the basal layer in the malignant diseases, whereas they were found only in the basal layer in the nonmalignant diseases. The results suggest that in human skin diseases, the extent of staining for PCNA, which is a cofactor of DNA polymerase-delta and is essential for cell proliferation, correlates with the extent to which the disease is treatment-resistant. In addition, our findings suggest that the PCNA LI and distribution of PCNA-positive cells in the skin may be helpful in the early diagnosis of skin malignancies.
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PMID:Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) in malignant and nonmalignant skin diseases. 1048 11

Ingenol 3-angelate (PEP005) is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. We report here that PEP005 also has potent antileukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary acute myeloid leukemia (AML) cells at nanomolar concentrations. Of importance, PEP005 did not induce apoptosis in normal CD34+ cord blood myeloblasts at up to 2-log concentrations higher than those required to induce cell death in primary AML cells. The effects of PEP005 were PKC dependent, and PEP005 efficacy correlated with expression of PKC-delta. The delta isoform of PKC plays a key role in apoptosis and is therefore a rational potential target for antileukemic therapies. Transfection of KG1a leukemia cells, which did not express PKC-delta or respond to PEP005, with enhanced green fluorescent protein (EGFP)-PKC-delta restored sensitivity to induction of apoptosis by PEP005. Our data therefore suggest that activation of PKC-delta provides a novel approach for treatment of acute myeloid leukemia and that screening for PKC-delta expression may identify patients for potential responsiveness to PEP005.
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PMID:PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. 1584 1

The sap of Euphorbia peplus, commonly know as 'petty spurge', 'radium weed' or 'milkweed' has been used for centuries as a traditional treatment for skin conditions, including warts, corns and cancers of the skin. Documentation of its use by medical professionals to treat basal cell carcinoma (BCC) dates from the early 19 century. Individuals who participated in a 1988 survey of home treatments for cancer indicated the sap of E. peplus was an effective cure for actinic lesions leading the investigators to suggest that this potential utility should be further explored in controlled clinical trials. The fractionation of the sap E. peplus using solvents of varying polarity yielded several macrocyclic diterpenes, many of which were found to have cytotoxic activity or the ability to influence cellular differentiation. Ultimately, ingenol 3-angelate (I3A) of PEP005, emerged as a promising potential new anti-cancer treatment. Here we report the proceedings from the First International Conference on PEP005, covering the exciting potential of PEP005 as the therapeutic agent for the treatment of skin cancer, leukemia and bladder cancer.
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PMID:Proceedings of the First International Conference on PEP005. 1726 70

The skin is an organ in which direct contact with viruses, solar UV irradiation and increased susceptibility to immune suppression gather to support viral tumorigenesis. Viruses transform keratinocytes by activation of cancer-promoting genes. Viral proteins may directly act as oncogenes that drive cells to proliferate or generate inflammatory responses and cause regeneration of injured cells that eventually lead to malignant transformation. Accelerated viral carcinogenesis is observed in the immune-deficient host. Decreased T-cell reactivity and lower number of antigen-presenting cells in the skin assist in viral escape and emergence of skin tumors. Three pathogenic human viruses associated with skin neoplasms are described: human papilloma virus (HPV), Kaposi's sarcoma (KS)-associated herpesvirus and human T-cell leukemia virus type 1. HPV was linked to squamous cell carcinoma (SCC) of the skin after its role in SCC of the cervix has been discovered. In the rare autosomal recessive epidermodysplasia verruciformis, an increased susceptibility to specific HPV strains initially results in widespread wart infection and later in life in the development of SCC over the sun-exposed skin. The role of HPV in nonmelanoma skin cancer of immune competent hosts is more difficult to prove. The discovery of human herpesvirus 8 as the causative pathogen of KS was made following the AIDS epidemic, and its role in all clinical variants of this tumor was confirmed. KS-associated herpesvirus exerts its tumorigenic effect through a wide repertoire of genes that regulate angiogenesis, inflammation, and cell cycle. Human T-cell leukemia virus type 1 causes adult T-cell leukemia and is often associated with skin eruptions that share common features with cutaneous T-cell lymphoma. In summary, studies of oncogenic viruses shed light on molecular mechanisms leading to tumor formation and aid in recognition of new pathways of carcinogenesis.
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PMID:Viral carcinogenesis in skin cancer. 1764 89

Disseminated Mycobacterium avium complex (MAC) infection is a rare but severe disease mostly seen in patients with AIDS. It has been previously described in patients suffering from other kinds of immunodeficiency (e.g. primary immunodeficiency diseases in children or hairy cell leukaemia). We report two cases of disseminated MAC disease in young women with extended granulomatosis that revealed a new form of severe immunodeficiency syndrome. Both clinical observations initially appeared to be very similar to WHIM syndrome (Warts, Hypogammaglobulinemia, Infection, Myelokathexis), a rare immunodeficiency disease correlated with CXC chemokine receptor 4 (CXCR4) mutation leading to an impaired internalization of the receptor upon its ligand CXCL12. We investigated the CXCR4 status of the lymphocytes in both patients and found a severe defect in CXCL12-promoted internalization but no mutation of its gene. Moreover, myelokathexis was not noted in bone marrow biopsies and therefore a diagnosis of WHIM syndrome could not be assessed. This immunodeficiency syndrome associated with CXCR4 dysfunction was responsible for severe MAC infection in our patients, with a fatal outcome in one case. It may be possible that these patients would have benefited from early antimycobacterial infection or azythromycin prophylaxis.
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PMID:Two cases of disseminated Mycobacterium avium infection associated with a new immunodeficiency syndrome related to CXCR4 dysfunctions. 2014 20

The WW-domain containing protein KIBRA has recently been identified as a new member of the Salvador/Warts/Hippo (SWH) pathway in Drosophila and is shown to act as a tumor suppressor gene in Drosophila. This pathway is conserved in humans and members of the pathway have been shown to act as tumor suppressor genes in mammalian systems. We determined the methylation status of the 5' CpG island associated with the KIBRA gene in human cancers. In a large panel of cancer cell lines representing common epithelial cancers KIBRA was unmethylated. But in pediatric acute lymphocytic leukemia (ALL) cell lines KIBRA showed frequent hypermethylation and silencing of gene expression, which could be reversed by treatment with 5-aza-2'-deoxycytidine. In ALL patient samples KIBRA was methylated in 70% B-ALL but was methylated in < 20% T-ALL leukemia (p = 0.0019). In B-ALL KIBRA methylation was associated with ETV6/RUNX1 [t(12;21) (p13;q22)] chromosomal translocation (p = 0.0082) phenotype, suggesting that KIBRA may play an important role in t(12;21) leukemogenesis. In ALL paired samples at diagnosis and remission KIBRA methylation was seen in diagnostic but not in any of the remission samples accompanied by loss of KIBRA expression in disease state compared to patients in remission. Hence KIBRA methylation occurs frequently in B-cell acute lymphocytic leukemia but not in epithelial cancers and is linked to specific genetic event in B-ALL.
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PMID:Frequent epigenetic inactivation of KIBRA, an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network, is associated with specific genetic event in B-cell acute lymphocytic leukemia. 2117 72

Infection with certain human papillomavirus types induces warts with specific macroscopic and microscopic features. We observed multiple flat wart-like lesions on the chest, neck and extremities of an adult T-cell leukemia patient. Histologically, atypical intracytoplasmic inclusion bodies currently known to be pathognomonic for genus gamma or mu papillomaviruses were disclosed in some cells of the epidermis showing histological features compatible with flat warts. In the present study, a novel human papillomavirus was identified and its whole genome, 7326 bp in length, was cloned and characterized. Phylogenetic analysis showed the virus designated as HPV126 to be a novel type of genus gamma papillomavirus. Strikingly, Ki-67 and p53 expression was found to be increased in all layers of the epidermis except for horny layer, contrasting to expression restricted to the basal and lower spinous layers in ordinary flat warts.
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PMID:Molecular cloning and characterization of a novel human papillomavirus, HPV 126, isolated from a flat wart-like lesion with intracytoplasmic inclusion bodies and a peculiar distribution of Ki-67 and p53. 2205 88

Human papillomaviruses (HPV) induce warts and cancers on skin and mucosa. The HPV16 capsid is composed of the proteins L1 and L2. After cell entry and virus disassembly, the L2 protein accompanies the viral DNA to promyelocytic leukaemia nuclear bodies (PML-NBs) within the host nuclei enabling viral transcription and replication. Multiple components of PML-NBs are regulated by small ubiquitin-like modifiers (SUMOs) either based on covalent SUMO modification (SUMOylation), or based on non-covalent SUMO interaction via SUMO interacting motifs (SIMs). We show here that the HPV16 L2 comprises at least one SIM, which is crucial for the L2 interaction with SUMO2 in immunoprecipitation and colocalization with SUMO2 in PML-NBs. Biophysical analysis confirmed a direct L2 interaction with SUMO substantiated by identification of potential L2-SUMO interaction structures in molecular dynamics simulations. Mutation of the SIM resulted in absence of the L2-DNA complex at PML-NB and in a loss of infectivity of mutant HPV16 pseudoviruses. In contrast, we found that L2 SUMOylation has no effect on L2 localization in PML-NBs and SUMO interaction. Our data suggest that the L2 SIM is important for L2 interaction with SUMO and/or SUMOylated proteins, which is indispensable for the delivery of viral DNA to PML-NBs and efficient HPV infection.
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PMID:An L2 SUMO interacting motif is important for PML localization and infection of human papillomavirus type 16. 2444 61

CXCR4(WHIM) somatic mutations are common Waldenstrom's Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis), CXCR(S338X) mutation in WM. Following SDF-1a stimulation, CXCR4(S338X) WM cells exhibited decreased receptor internalization, enhanced and sustained AKT kinase (AKT) and extracellular regulated kinase (ERK) signaling, decreased poly (ADP-ribose) polymerase and caspase 3 cleavage, and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4(S338X)-related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a-treated CXCR4(S338X) WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4(WT) cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a-treated CXCR4(S338X) WM cells demonstrating their role in SDF-1a-mediated ibrutinib resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4(WHIM) versus CXCR4(WT) WM patients, and remained active despite ibrutinib therapy in CXCR4(WHIM) patients. Last, CXCR4(S338X) WM cells showed varying levels of resistance to other WM relevant therapeutics, including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4(WHIM) mutations, and provide a framework for investigation of CXCR4 inhibitors in WM.
Leukemia 2015 Jan
PMID:The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia. 2491 31


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