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Familial Acute Myeloid Leukemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The molecular genetic aberration underlying familial platelet disorders with propensity to myeloid malignancies [online Mendelian inheritance in man (OMIM) #601399] including acute myeloid leukemia (FPD/AML) was identified in 1999 as germline mutations in the RUNX1 gene [6], located in chromosome 21q22.12 band at the breakpoint in the t(8;21) translocation, the source from where RUNXI was originally cloned [28]. RUNX1, previously known as AML1, is critical for embryogenesis and hematopoiesis [29]. For the latter functions, RUNX1 encodes for a protein that complexes with core binding factor β to form a heterodimeric core binding factor complex that regulates the expression of several genes critical for hematopoiesis [30]. In FPD/AML, mutations located in the highly conserved runt homology domain of the RUNX1 gene cause a loss of RUNX1 function and are associated with a high incidence of hematologic myeloid malignancies including myelodysplasia and acute myeloid leukemia [31], and with a lower incidence of lymphoid malignancies including acute lymphoblastic leukemia and hairy cell leukemia [32,33]. At least 40 different mutations have been identified thus far in individuals with FPD/AML, with the majority being missense, and including nonsense, insertions, deletions, or splice site mutations [34].
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
H3K9 methylation, particularly trimethylation, is believed to be crucial to formation of heterochromatin (80), particularly as this methylation creates a binding site for the chromodomain (chromatin organization modifier) of the repression related protein HP1. Trimethylation at H3K9 is achieved by Suv39h1/Suv39h2 (94) which was the first HMT identified. This process is involved in several tumor-related signaling pathways, such as suppression achieved by Smads after TGF-b signaling (95), or suppression of cyclin E and E2F by Rb protein, the latter losing this suppressive ability when mutated (96,97). Relevant to our argument is that this repression requires the recruitment of HDACs (98). Furthermore, it appears that this Suv39h-HP1-mediated mechanism is intimately involved with DNMT3A and DNMT3B DNA methylating activity (99). It is worth noting that mice with decreased levels of Suv39h1 showed a high incidence of B-cell lymphomas (94). Of particular interest with regard to leukemia, it has been shown that residues 380–432 and 351–381 in the RUNX1 transcription factor, bind Suv39h1 as well as HDAC1 and 3 (100). RUNX1 is a component of fusion proteins found frequently in AML, such as t(8;21), t(12;21), and related to the activity inv(16); this relationship to H3K9 methylation may explain the release of lysosomal repression in cells with these mutations upon treatment with HDACi and hypomethylating agents (101). SETDB1, another enzyme which di- and trimethylates histones at H3K9, also interacts directly with DNMT3A and DNMT3B (102).
Resistance Mechanisms of Tumor Cells
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
In the hematopoietic system, other proteins are also able to exhibit these features. The EGR1 transcription factor (as well as EGR2 or EGR3) allows stem cells to go into homeostasis or dormancy to maintain them (Min et al., 2008; reviewed in Kühn et al., 2016). EGR1 has initially identified as activator of p21 and as gatekeeper of the TP53 (Krones-Herzig et al., 2003). Cells (over)expressing EGR1 protein can potentially escape treatment, and are presumably one of the reasons for relapses. A dormant cell needs only to switch back from this dormant state to the normal growth program. Recently, it has been shown that CDK4 but mainly overexpressed CDK6 (under certain stress conditions) re-activates dormant stem cells and causes tumor cell formation (Scheicher et al., 2015). Similarly, other factors have been described, such as HOXB4 (an OCT4 and GATA2 downstream target gene; Huang et al., 2016), which is capable of inducing sufficient amounts of the RUNX1 transcription factor to maintain hematopoietic stem cells (Teichweyde et al., 2017).
Acute myeloid leukemia in a child with familial platelet disorder and a cryptic runx1 intragenic deletion
Published in Pediatric Hematology and Oncology, 2022
Lois M. Dodson, Kristen J. Kurtz, Andrea N. Marcogliese, Brian D. Friend, Alexandra M. Stevens, Kevin E. Fisher
The RUNX1 intragenic deletion was initially missed by in-house analysis and reference laboratory testing. The clinical history of thrombocytopenia informed manual review of the RUNX1 sequencing data. Rare RUNX1 intragenic deletions in patients with FPD-MM that were “negative by NGS” but detected by CMA are reported.5,6 Most clinical and reference laboratory targeted NGS tests are optimized to assess for single nucleotide variants (SNVs) and small indels.7 Notably, a vast majority of the >130 pathogenic germline RUNX1 variants described in FDP-MM are missense, splice site, nonsense, or frameshift mutations that result in SNVs or small (<25bp) insertions and deletions (indels).8,9 Exon-level deletions are difficult to detect without optimized variant calling; multiplex ligation-dependent probe amplification or high-density CMA are superior detection methods.10 Thus, for patients with wild-type RUNX1 sequencing results and clinical suspicion of FDP-MM, exon-level deletions should be definitively ruled-out with additional testing, and the true incidence of RUNX1 intragenic deletions in FPD-MM also warrants additional study. Furthermore, both somatic and germline RUNX1 mutations occur in pediatric AML.11 Testing of a non-tumor sample is required not only to determine the origin and confirm the diagnosis of FPD-MM, but also for familial genetic counseling and assessment of suitability for bone marrow transplant from a RUNX1 wild-type donor.
Molecular Genetics of Cleidocranial Dysplasia
Published in Fetal and Pediatric Pathology, 2021
Jamshid Motaei, Arash Salmaninejad, Ebrahim Jamali, Imaneh Khorsand, Mohammad Ahmadvand, Sasan Shabani, Farshid Karimi, Mohammad Sadegh Nazari, Golsa Ketabchi, Fatemeh Naqipour
Thirty percent of patients with acute myeloid leukemia (AML) and ten percent of patients with myelodysplasia (MDS) have mutations in the RUNX1 gene [12]. RUNX1 plays an important role in hematopoietic cells. Hereditary mutation in RUNX1 causes familial platelet disorder with predisposition to myeloid malignancy (FPD/AML) with autosomal dominate inheritance pattern [13]. RUNX2 plays an important role in the development of the skeletal system and the morphogenesis of other organs, such as thyroid and breast. The role of RUNX2 is increasingly recognized in various cancers, including thyroid, prostate, lung and breast cancer. Many studies have shown that the deregulation of RUNX2 is associated with the progression and metastasis of various tumors [14–17]. RUNX3 is a tumor suppressor gene that plays a role in various biological processes, including development of the cranial and dorsal root ganglia, gastrointestinal tract and T-cell differentiation. Mutations in RUNX3 have been reported in various diseases including colon and gastric cancers, glioma, melanoma, prostate cancer, renal cell carcinoma and neural disorders [18].
Prognostic effect of RUNX1 mutations in myelodysplastic syndromes: a meta-analysis
Published in Hematology, 2020
Wei He, Caifang Zhao, Huixian Hu
RUNX1, as a transcription factor, is an important regulator of embryogenesis and definitive hematopoiesis in vertebrates. Germline mutations of RUNX1 might result in familial platelet disorder with potential progression to AML. The target genes regulated by RUNX1 are essential for hematopoietic differentiation, ribosome biogenesis, cell cycle regulation, and p53 and transforming growth factor β signaling pathways [33,34]. The normal function could be disrupted by point mutation. This could lead to (a) abrogation of stem cell function, (b) damage of cell cycle genomic instability, (c) inhibition of p53 signaling and apoptosis, (d) activation of oncogenic signaling pathways, (e) suppression of ribosomal biogenesis, and (f) hypoxic microenvironment metabolism alterations [35]. Ultimately, the development of hematological malignancies was triggered. Indeed, RUNX mutations, like mutations in other transcription factors, are often acquired later during the evolution from MDS to sAML for the mutations are more common in sAML [36].