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Sotos Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Of >300 different mutations associated with Sotos syndrome identified to date, gross deletions (e.g., 5q35 microdeletion, which is identified in 50% of Japanese and Korean patients but <15% in patients from other parts of the world), small indels, point mutations (15%), and splice-site mutations dominate. These include 521T>A (V174A), 607G>A (V203I) and 896delC (frameshift) in exon 2, 2333T>G (L778X) and 2386–2389delGAAA (frameshift) in exon 5, 3882delT (frameshift) in exon 6, 4417C>T (R1473X) in exon 10, 4779–4781delTTTinsATTC (frameshift) and 4855T>C (C1619R) in exon 13, IVS13 + 1G>A (skip exon) in intron 13, 4987C>T (R1663C) in exon 14, 5375G>T (G1792V) in exon 16, 5737A>G (N1913D) in exon 18, 6115C>T (R2039C) in exon 20, 6241T>G (L2081V) in exon 21, 6291delG (frameshift), 6356delA (D2119V), 6370T>C (C2124R), and A6442delAGCGACCA (K2151fsX) in exon 22, and 6523T>A (C2175S), 6532delTGCCCCAGC (2178–2180delCPS), 6614A>G (H2205R), 6605G>A (C2202Y), and 7576C>T (P2526S) in exon 23. Indeed, several missense-mutations target the PHDV-C5HCHNSD1 tandem domain, which is composed by a classical (PHDV) and an atypical (C5HCH) PHD finger, impairing NSD1 interactions with cofactors such as Nizp1 and thus impacting on the repression of growth-promoting genes, leading to overgrowth conditions [9].
TP53 in cancer origin and treatment
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Elena A. Komarova, Peter M. Chumakov, Andrei V. Gudkov
Besides ARF, TP53 has other cellular counterparts that may be involved in its function. For example, CBP/p300 (Gu et al., 1997; Lill et al., 1997) and p33 (ING1) (Garkavtsev et al., 1998), a nuclear PHD finger protein, are required for TP53 to function as a transcription activator, while REF1 is involved in TP53-mediated apoptosis (Jayaraman et al., 1997).
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Primarily, the H3K4me3 distribution is thoroughly coupled to CpG-dependent dinucleotide repeated units present in CpG islands. Predominately, unmethylated GC-dense DNA and CpG- regions are found at promoter regions in 50–70% of vertebrates [24]. The discovery of Zn-finger CxxC is usually found in SETD1A/B subunit CFP1 and in MLL1/2, which elucidated the presence of a biochemical link between promoters of CpGI and H3K4me3 [2] (Figure 3.3). Promoters of CPGI are marked with the presence of H3K4me3 strongly correlated to the activity of genes [25,26]. In addition, emerging evidence illustrates that MLL2 is highly responsible in order to maintain H3K4me3 in vivo at CpGI promoters along with reduce expression [27,28]. Although CEPI, a specific subunit of SETD1, is more preferentially enriched in the higher H3K4me3 levels and mostly found at the most of active regions of gene promoter [29]. CpGI promoters started showing linkage with them in regulated developmental genes, which possess bivalent structure and play a role in harboring the H3K4me3 repressive marks and H3K4me2 [30]. Interestingly, H3K4me3 writers’ ability to sample the genome of CpGI is wide. It has also been found that H3K4me3 presence at promoters of CpGI might act as poison for the silent genes that cause rapid activation of these genes upon differentiation. The binding in between the complex of SETD1/MLL might reinforce their strong binding by means of recognition of the presence of their specific own marks, such as H3K4me3. CFP1 having PHD finger domain, known explicitly for its role in H3K4me3 read, also found that it displays its potent role in mediating the interaction between SETDI and H3K4me3 [31–33]. In Hox Locus, the recruitment of MLLI to the specific target sites is usually carried out through the presence of MLL1 containing its third domain, which is more important in the case of H3K4me3 binding [34].
Clinical characteristics and prognostic study of adult acute myeloid leukemia patients with ASXL1 mutations
Published in Hematology, 2020
Yun Lin, Yaping Wang, Yi Zheng, Zechuan Wang, Yanni Wang, Shaoyuan Wang
We detected mutations of exon14 and exon15 in FLT3-ITD gene, mutations of exon12 in NPM1 gene, mutations of exon17 in C-kitD816, mutations in CEBPA, mutations of exon4in IDH1/IDH2, mutations in dupMLL, mutations of exon2, 4, 7, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23 and the surrounding intron areas in DNMT3A gene, mutations of exon2–10 and the surrounding intron areas in 6 PHD finger protein (PHF6) gene, mutations of exon1–10 and the surrounding intron areas in TET2, mutations of exon12 in ASXL1 gene. The clinical data of patients when first diagnosed with AML between January 2013 and August 2015, including initial white blood cell counts in peripheral, proportion of immature cells in peripheral blood, platelet and hemoglobin counts, the serum levels of lactate of dehydrogenase, uric acid and α-HBAD, chromosome classification, the data of bone marrow examinations were collected. The chemotherapy regiments reduced time and recurrence time was also collected. The clinical outcome of enrolled patients was also traced.
ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival
Published in Current Medical Research and Opinion, 2018
Juliana Alvarez Argote, Constantin A. Dasanu
ASXL1 comprises 13 exons located in chromosome band 20q11. It encodes a member of the polycomb family of the chromatin binding proteins and is involved in epigenetic regulation of gene expression via its C-terminal plant homeodomain (PHD) finger (Figure 1)6. Although the PHD finger is located within the exon 12 of ASXL1, it is important to recognize that it represents just a small portion of the exon 12. The PHD finger interacts with the polycomb group repressive complex protein (PRC1 and PRC2) and other transcription activators and repressors to exert its function in regulating chromatin17–21. Data suggests that ASXL1 mutations associated with myeloid neoplasms display a truncation in exon 12, adjacent to the PHD finger22–24. In addition, in vitro studies in leukemic cells suggest that there is a loss of ASXL1 protein expression when ASXL1 mutations are detected in myeloid neoplasms24. The most common ASXL1 mutation found in patients with myeloid neoplasms is c.1934dupG;p.G646WfsX12 that accounts for more than 50% of cases17–19,25.
Molecular features, prognosis, and novel treatment options for pediatric acute megakaryoblastic leukemia
Published in Expert Review of Hematology, 2019
Federico De Marchi, Marito Araki, Norio Komatsu
NUP98–KDM5A cryptic translocation induces leukemia proliferation when introduced into murine bone marrow [50]. NUP98 is a member of nucleoporin family with transactivating properties [45], and KDM5A is a HEK4me3-binding PHD finger, which can activate genes involved in mixed lineage leukemia (MLL)-rearranged leukemia (Figure 1), as proven by co-immunoprecipitation assays [51]. KMT2A rearrangement may involve different fusion partners, and its presence has been described in several cases of pediatric leukemia [52]. 7-monosomy is a known marker of poor prognosis in adult AML [53].