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Schinzel−Giedion Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
In contrast to germline variants that are responsible for the onset of SGS and increased risk for embryonal tumors, somatic SETBP1 mutations tend to occur in patients with hematologic neoplasms, including acute myeloid leukemia (AML, <1% of cases), myeloproliferative neoplasm (MPN, 4%), myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes (MDS/MPN, 9%), myelodysplastic syndrome (MDS, 2–3%), juvenile myelomonocytic leukemia (JMML, 8–10%), chronic myelomonocytic leukemia (CMML, 15–19%), chronic neutrophilic leukemia (CNL, 10–38%), and atypical chronic myeloid leukemia (aCML, 30%) [4–16]. Most cases are associated with heterozygous missense mutations, and only a few cases show a homozygous mutation. SETBP1 involvement in leukemia transformation is mainly through activation of the HOXA9 and HOXA10 genes, and subsequent increase in leukemic cell proliferation [17]. Somatic SETBP1 mutations observed in hematologic neoplasms appear to have a gain-of-function effect on the SETBP1 protein, leading to decreased binding of the βTrCP1 and increased protein levels. The somatic variants in hematologic neoplasms appear more disruptive than the germline variants in SGS, and patients with myeloid malignancies harboring SETBP1-mutations often have a significantly inferior overall survival and increased risk of disease progression [18–20].
DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jesus Duque, Michael Lübbert, Mark Kirschbaum
Histone methylation is a marker of both active and inactive genes. Trimethylation of lysine 4 in H3K4 is linked to activated genes (79,80). Methylation at this site is associated with multiple other modifications such as acetylation by acetyltransferases (81) and deacetylation by deacetylases, the latter activity perhaps acting as a brake on genes actively transcribed by H3K4 methylation (82). On the other hand, some H3K4 interactions are specific for unmethylated DNA. The MLL enzymes, which can polymethylate H3K4 (83,84), exist as multicomponent complexes containing differing catalytic SET-related units (85). MLL1 in particular interacts with other modifiers such as the acetylases MOF and CBP (86), and along with other MLL enzymes also recruits the homeobox family genes. The Hox transcription factors play a role in embryonic development, as well as in angiogenesis, in which HoxD3, HoxB3, and HoxA9 are essential regulators. MLL1 is responsible for H3K4 trimethylation at the HoxA9 locus (86). It has recently been shown that suppression of MLL will inhibit Hox-related proangiogenic activity (87). A necessary component of the MLL complex that regulates Hox gene expression is menin, which specifically associates with MLL proteins among SET1 homologs. Menin is the protein encoded by Men1, which when mutated leads to multiple neoplasms, particularly in endocrine tissue (88). Hox gene expression is dependent upon the association of menin with MLL (89).
Collection and Expansion of Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Recent data indicate that a variety of regulatory molecules that are active in early development, homeobox (HOX) transcription factors, may also play a role in the maintenance of stem cell self-renewal. Multiple HOX family members are expressed in the most primitive hematopoietic stem cell-enriched populations and their expression is down regulated in terminally differentiating CD34- cells.63 Overexpression of the homeobox gene, Hoxb4, in murine64-66 and human cord blood67 stem cells leads to enhanced proliferation of clonogenic progenitors in vitro and an enhanced ability to regenerate the most primitive stem cell compartment following serial transplantation in mice. Importantly, none of the mice in these experiments demonstrated hematological abnormalities following transplantation. HOXB4-transduced murine bone marrow cells led to rapid, extensive and highly polyclonal stem cell expansion in vitro resulting in a 1000-fold net increase of stem cells that retained full lymph-myeloid repopulating potential.68 Together these data suggest that HOXB4 overexpression enhances the rate of stem cell expansion without impairing normal differentiation or causing transformation. Other members of the HOX family, including HOXC4,69 HOXa9,70 LIM-homeobox 2 (LH2)71 and HOX1172 have been shown to have similar effects as HOX4B on stem and early progenitor cell expansion, but in some cases led to immortalization71,72 or transformation70 after prolonged expression. Recent review articles provide an extensive description of the role of HOX genes in normal hematopoiesis and leukemogenesis.73,74 Together these findings suggest exciting new areas for genetic manipulation of HOX genes in hematopoietic stem cell regulation, and in the case of HOXB4, perhaps for therapeutic stem cell expansion.
Role of Vitamin E in Selected Malignant Neoplasms in Women
Published in Nutrition and Cancer, 2022
Anna Markowska, Michał Antoszczak, Janina Markowska, Adam Huczyński
In 2019, the results of phase II studies on the use of δTT in combination with the anti-angiogenic drug bevacizumab in women with recurrent chemotherapy-resistant OC were announced (48). Treatment response was based on standard RECIST 1.1 and serum CA125 levels. The study included 23 patients, among whom serous cancer was predominant (over 90% of cases), mostly FIGO stage III (16 cases, 70%); maturity was mainly G2 and G3 (eight cases, 35% and 11 cases, 48%, respectively). The study measured the level of methylated DNA (HOXA9 meth-ctDNA) in the serum after one cycle of chemotherapy. Abnormal DNA methylation occurs in almost all malignant tumors, and methylated DNA is tumor specific; HOXA9 expression encodes a DNA binding transcription factor that can regulate gene expression. The study showed a favorable therapeutic effect, namely, disease stabilization in 70% of patients; the median PFS was 6.9 mo, and the median OS was 10.9 mo. The toxicity of the applied therapy was defined as very low. The authors of the article believe that the combination of bevacizumab with δTT delivers a very beneficial therapeutic effect in patients, and the analysis of the HOXA9 meth-ctDNA level allows for the termination of previously ineffective treatment and the implementation of a new personalized therapy.
Homeobox A5 and A9 expression and beta-thalassemia
Published in British Journal of Biomedical Science, 2021
EAE Badr, IE-T El-Sayed, MKR Alasadi
Data from zebrafish point to Homeobox (Hox) genes having an important role in normal haematopoiesis related to haematopoietic stem cells (HSCs) and early haematopoietic progenitors [6]. The Hox genes contain several clusters (A-D). Each cluster consists of paralog groups with nine to eleven members assigned on the basis of sequence similarity and relative position within the cluster [7]. The HOXA family encodes proteins that contain the DNA-binding homeobox motif and controls the early patterns of embryo segmentation. Although HOX expression is typically inhibited in adults, reactivation may occur with various homoeostatic cellular processes including haematopoiesis. Hox genes are required for the maintenance of progenitor or stem cell status, promoting their proliferation. HoxA9 is the most preferentially expressed Hox gene in human CD34+ HSCs and early haematopoietic progenitors [8]. HoxA5 has two effects on erythropoiesis: it causes a predominance of mature erythroid lineage cells and the partial apoptosis of erythroid progenitors. RNA-seq indicates that multiple biological processes including erythrocyte homoeostasis, cell metabolism, and apoptosis are modified by HoxA5 [9]. We hypothesized roles for HoxA9 and HoxA5 in β-thalassemia.
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
DHODH was identified as a target for AML through a large screen of small molecule inhibitors on HoxA9-overexpressed myeloid cells [124]. The transcription factor HoxA9 seems to at least partially regulate cellular differentiation of myeloid precursor cells; its downregulation leads to differentiation of myeloblasts [124]. Inducing cellular differentiation rather than purely triggering apoptosis presents an attractive mechanism to target myeloblasts, and this is effectively employed in the treatment of acute promyelocytic leukemia with ATRA and IDH-mutated AML with IDH-inhibitors [14,125–127]. In order to study myeloid differentiation and leukemogenesis, HoxA9 was overexpressed in murine hematopoietic cells, which eventually led to the development of immortalized myeloblasts [124]. Upon induction of cellular differentiation by a small molecule inhibitor, the myeloblasts would terminally differentiate into polymorphonuclear cells [124]. The immortalized myeloblasts were screened against a library of over 330,000 small molecule inhibitors and differentiation status was assessed [124]. Twelve compounds from the library were identified to reproducibly induce myeloid differentiation, and 11 of the 12 molecules were found to be inhibitors of the enzyme DHODH [124].