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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).
Blastic Transformation of Chronic Myelogenous Leukemia: Does BCR-ABL Orchestrate Disease Progression?
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
Calabretta Bruno, Perrotti Danilo
Two other genes upregulated by BCR-ABL in CML-BC are Evi-1 and HOXA9, two transcription factors which can cooperate with BCR-ABL in blocking myeloid differentiation and enhancing the proliferative and survival advantage of BCR-ABL-expressing cells (85,86). Perhaps, the cumulative effect of MYC, mdm2, Evi-1, HoxA9, and other BCR-ABL targets involved in proliferation, survival and differentiation coupled with loss of PP2A tumor suppressor activity and downregulation of C/EBPα leads incrementally to differentiation arrest, reduced apoptosis susceptibility, and enhanced proliferative potential of CML blast crisis cells.
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].
Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia
Published in Expert Opinion on Investigational Drugs, 2018
Sushma Bartaula-Brevik, Marte Karen Lindstad Brattås, Tor Henrik Anderson Tvedt, Håkon Reikvam, Øystein Bruserud
Previous studies of murine AML suggest that Hoxa9/Hoxa10 (see discussion earlier) are involved in leukemogenesis through their effects on the expression of αvβ3 integrins and SYK expression/activation [48] (see also Section 5.3). Furthermore, studies of human AML suggest that Hox genes are important in leukemogenesis and high Hox expression seems to identify a distinct patient subset [49,50]. Similar to the murine AML models [48], Hox expression seems to be associated with high expression of FGF2, αvβ3 integrins, and Cdx4, and such patients are also characterized by a higher proliferative GM-CSF response and a stronger antiproliferative effect of FGF2 and SYK inhibition [48]. Thus, the Hox/FGF2/β-catenin/Cdx4 together with the Hox/αvβ3/SYK cooperation first identified in murine AML models seem important also in human leukemogenesis at least for a subset of patients, especially patients with intermediate cytogenetics [49].