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Other entities represented in this entry:
HGNC Approved Gene Symbol: RUNX1
SNOMEDCT: 725034002;
Cytogenetic location: 21q22.12 Genomic coordinates (GRCh38): 21:34,787,801-35,049,302 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.12 | Leukemia, acute myeloid | 601626 | Autosomal dominant; Somatic mutation | 3 |
| Platelet disorder, familial, with associated myeloid malignancy | 601399 | Autosomal dominant | 3 |
The RUNX1 gene encodes a Runt-related transcription factor, which is part of the RUNX gene family (see RUNX2, 600211 and RUNX3, 600210). The RUNX transcription factors are composed of an alpha subunit, encoded by the RUNX1, RUNX2, and RUNX3 genes, which binds to DNA via a Runt domain, and a beta subunit, encoded by the CBFB gene (121360), which increases the affinity of the alpha subunit for DNA but shows no DNA binding by itself. These proteins have a conserved 128-amino acid Runt domain, so called because of its homology to the pair-rule gene runt, which plays a role in the segmented body patterning of Drosophila. RUNX1 has a primary role in the development of all hematopoietic cell types; is required for CD8 T-cell development during thymopoiesis; determines the nociceptive sensory neuron phenotype; plays a supportive role in bone formation; and can produce oncogenic transformation to acute myelogenous leukemia (AML; 601626) (review by Cohen, 2009). RUNX1 was originally identified as PEBP2, a polyomavirus enhancer-binding protein (Zhang et al., 1997).
According to the French-American-British (FAB) classification, the t(8;21)(q22;q22) translocation is one of the most frequent karyotypic abnormalities in acute myeloid leukemia (AML; 601626), especially in the M2 subtype. Miyoshi et al. (1991) isolated and sequenced cDNA clones for a gene they named AML1, on chromosome 21, that was rearranged by the t(8;21) translocation.
Miyoshi et al. (1995) cloned variants of AML1 from several cDNA libraries, including a Burkitt lymphoma cDNA library. The predicted AML1 proteins contain 453 and 480 amino acids and were designated AML1b and AML1c, respectively. The N terminus of AML1b differs from that of AML1c, but it is identical to the N terminus of the 250-amino acid AML1 protein reported by Miyoshi et al. (1991), which was renamed AML1a. All 3 proteins contain the 128-amino acid Runt domain. AML1b and AML1c also contain a large C-terminal region that is likely a transcriptional activation domain. Miyoshi et al. (1995) determined that the AML1c transcript begins with exon 1 of the AML1 gene, while AML1a and AML1b begin at exon 3, probably due to utilization of an alternative promoter. Northern blot analysis detected 6 major transcripts of 2.2 to 7.5 kb encoding AML1b and AML1c. The transcripts could be explained by the existence of 2 promoters, alternative splicing, and differential usage of 3 polyadenylation sites. Expression of the transcripts was detected in all tissues examined except brain and heart; however, the expression levels of the transcripts differed between tissues. The ratio of AML1c transcripts to AML1b transcripts was higher in thymus and spleen than in other tissues.
Using a cDNA containing the Runt domain-encoding region of mouse Aml1 to screen a human T-cell cDNA library, Zhang et al. (1997) cloned a minor splice variant of AML1, designated AML1-delta-N, produced by splicing exon 1 directly to exon 4. The deduced 348-amino acid protein has an N-terminal truncation and lacks about half of the Runt domain. RNase protection assays detected AML1-delta-N in all hematopoietic cell lines examined of lymphoid to myeloid origin. Western blot analysis showed that AML1-delta-N was translated into a 43-kD protein in vitro and in vivo. Transfected mouse fibroblasts expressed AML1-delta-N mainly in the nucleus.
Levanon et al. (2001) identified 12 alternatively spliced RUNX1 cDNAs that differ in their 5-prime and 3-prime ends. The proteins range in size from 20 to 52 kD, and all contain a DNA-binding Runt domain.
Zhang et al. (1997) found that the AML1-delta-N variant of AML1, which lacks part of the Runt domain, neither bound to DNA nor heterodimerized with the beta subunit of PEBP2. AML1-delta-N interfered with the transactivation activity of PEBP2. Stable expression in a mouse myeloid cell line blocked granulocytic differentiation in response to granulocyte colony-stimulating factor (138970). Zhang et al. (1997) concluded that AML1-delta-N is a modulator of AML1 function.
Taniuchi et al. (2002) showed that binding sites for Runt domain transcription factors are essential for CD4 (186940) transcriptional silencer function, and that different RUNX family members are required to fulfill unique functions at each stage. They found that RUNX1 is required for active repression in CD4-negative/CD8 (see 186910)-negative thymocytes, whereas RUNX3 is required for establishing epigenetic silencing in cytotoxic lineage thymocytes. Cytotoxic T cells deficient in Runx3, but not helper cells, had defective responses to antigen, suggesting that RUNX proteins have critical functions in lineage specification and homeostasis of CD8-lineage T lymphocytes.
Stein et al. (2004) reviewed the function of mammalian Runx proteins in osteogenesis. They stated that Runx2 (600211) is the principal osteogenic master switch, while Runx1 and Runx3 are expressed in bone cells and appear to support bone cell development and differentiation.
Cleary (1999) provided a discussion and diagram of the multiple routes to a common pathway in leukemias. The heterodimeric CBFA2/CBFB transcription factor complex binds core enhancer sequences (TGTGGT) in the regulatory regions of several genes that are important to hematopoietic cell differentiation. Chromosomal aberrations in specific subsets of leukemia target the genes encoding either subunit of the complex to create transdominant chimeric oncoproteins. Alternatively, acquired or germline mutations and deletions of CBFA2 abrogate CBFA2 function and negate its tumor-suppressor role.
Ono et al. (2007) demonstrated that the transcription factor AML1/RUNX1, which is crucially required for normal hematopoiesis including thymic T cell development, activates IL2 (147680) and IFN-gamma (147570) gene expression in conventional CD4+ T cells through binding to their respective promoters. In natural T(R) cells, FOXP3 (300292) interacts physically with AML1. Several lines of evidence supported a model in which the interaction suppresses IL2 and IFN-gamma production, upregulates T(R) cell-associated molecules, and exerts suppressive activity. Ono et al. (2007) concluded that this transcriptional control of T(R) cell function by an interaction between FOXP3 and AML1 can be exploited to control physiologic and pathologic T cell-mediated immune responses.
Chen et al. (2009) used conditional deletion to demonstrate that Runx1 activity in vascular endothelial cadherin (CDH5; 601120)-positive endothelial cells is indeed essential for intraarterial cluster, hematopoietic progenitor, and hematopoietic stem cell formation in mice. In contrast, Runx1 is not required in cells expressing Vav1 (164875), one of the first pan-hematopoietic genes expressed in hematopoietic stem cells. Chen et al. (2009) concluded that their data collectively showed that Runx1 function is essential in endothelial cells for hematopoietic progenitor and hematopoietic stem cell formation from the vasculature, but its requirement ends once or before Vav is expressed.
Lancrin et al. (2009) demonstrated that the hemangioblast generates hematopoietic cells through the formation of a hemogenic endothelium intermediate, providing the first direct link between the 2 precursor populations, hematopoietic and endothelial cells. The cell population containing the hemogenic endothelium is transiently generated during blast colony-forming cell development. The cell population is also present in gastrulating mouse embryos and generates hematopoietic cells on further culture. At the molecular level, Lancrin et al. (2009) demonstrated that the transcription factor Tal1 (187040) is indispensable for the establishment of this hemogenic endothelium population, whereas the core binding factor Runx1 is critical for generation of definitive hematopoietic cells from hemogenic endothelium. Lancrin et al. (2009) concluded that their results merged the 2 a priori conflicting theories on the origin of hematopoietic development into a single linear developmental process.
Using mouse embryonic stem cells differentiated in vitro, Adamo et al. (2009) demonstrated that fluid shear stress increased the expression of Runx1 in CD41+ c-Kit+ hematopoietic progenitor cells, concomitantly augmenting their hematopoietic colony-forming potential. Moreover, they found that shear stress increased hematopoietic colony-forming potential and expression of hematopoietic markers in the paraaortic splanchnopleura/aorta-gonads-mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear stress-induced signaling, compromised hematopoietic potential in vitro and in vivo. Adamo et al. (2009) concluded that their data revealed a critical role for biomechanical forces in hematopoietic development.
Bertrand et al. (2010) used the zebrafish embryo to image directly the generation of hematopoietic stem cells from the ventral wall of the dorsal aorta. Using combinations of fluorescent reporter transgenes, confocal time-lapse microscopy, and flow cytometry, Bertrand et al. (2010) identified and isolated the stepwise intermediates as aortic hemogenic endothelium transitions to nascent hematopoietic stem cells. Using a permanent lineage tracing strategy, Bertrand et al. (2010) demonstrated that the hematopoietic stem cells generated from hemogenic endothelium are the lineal founders of the adult hematopoietic system.
By noninvasive, high-resolution imaging of live zebrafish embryos, Kissa and Herbomel (2010) showed that hematopoietic stem cells emerge directly from the aortic floor, through a stereotyped process that does not involve cell division but a strong bending then egress of single endothelial cells from the aortic ventral wall into the subaortic space, and their concomitant transformation into hematopoietic cells. The process is polarized not only in the dorsoventral but also in the rostrocaudal versus mediolateral direction, and depends on Runx1 expression: in Runx1-deficient embryos, the exit events are initially similar, but much rarer, and abort into violent death of the exiting cell. Kissa and Herbomel (2010) concluded that the aortic floor is hemogenic and that hematopoietic stem cells emerge from it into the subaortic space, not by asymmetric cell division but through a new type of cell behavior, which they called an endothelial hematopoietic transition.
Boisett et al. (2010) used time-lapse confocal imaging and a new dissection procedure to visualize the deeply located aorta of the mouse embryo. They showed the dynamic de novo emergence of phenotypically defined hematopoietic stem cells (Sca1-positive, c-kit-positive, CD41-positive) directly from ventral aortic hemogenic endothelial cells.
Using fate mapping analysis, Ginhoux et al. (2010) determined that adult microglia derive from primitive macrophages. Ginhoux et al. (2010) showed that microglia develop in mice that lack colony-stimulating factor-1 (CSF1; 120420) but are absent in Csf1 receptor (CSF1R; 164770)-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors expressing Runx1 that arise before embryonic day 8. Ginhoux et al. (2010) concluded that their results identified microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
Kwiatkowski et al. (2014) presented the discovery and characterization of a covalent CDK7 (601955) inhibitor, THZ1, which had the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell line profiling indicated that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukemia (T-ALL), have exceptional sensitivity to THZ1. Genomewide analysis in Jurkat T-ALL cells showed that THZ1 disproportionately affects transcription of RUNX1 and suggested that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 superenhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumor cells. Kwiatkowski et al. (2014) concluded that pharmacologic modulation of CDK7 kinase activity may provide an approach to identify and treat tumor types that are dependent on transcription for maintenance of the oncogenic state.
AML1/ETO Fusion Protein
Evidence from several sources indicates that targeting of gene regulatory factors to specific intranuclear sites may be critical for the accurate control of gene expression. McNeil et al. (1999) reported that substitution of the chromosome 8-derived ETO protein (133435) for the multifunctional C terminus of AML1 precluded targeting of the factor to AML1 subnuclear domains. Instead, the AML1/ETO fusion protein was redirected by the ETO component to alternate nuclear matrix-associated foci. They concluded that misrouting of gene regulatory factors as a consequence of chromosomal translocations is an important characteristic of acute leukemias.
Retinoic acid receptor (RAR; see 180240) and AML1 transcription factors are found in leukemias as fusion proteins with PML (102578) and ETO, respectively. Association of PML-RAR and AML1-ETO with the nuclear corepressor (NCOR; see 600849)/histone deacetylase (HDAC; see 601241) complex is required to block hematopoietic differentiation. Minucci et al. (2000) showed that PML-RAR and AML1-ETO exist in vivo within high molecular weight nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of NCOR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results showed that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation.
The myeloid transcription factor CEBPA (116897) is crucial for normal granulopoiesis, and dominant-negative mutations of the CEBPA gene are found in a significant proportion of patients with myeloblastic subtypes (M1 and M2) of AML. Pabst et al. (2001) demonstrated that the AML1-ETO fusion protein suppresses CEBPA expression.
Zhang et al. (2004) showed that AML1/ETO, as well as ETO, inhibits transcriptional activation by E proteins (see 147141) through stable interactions that preclude recruitment of p300 (602700)/CREB-binding protein (CBP; 600140) coactivators. These interactions are mediated by a conserved ETO TAF4 (601796) homology domain and a 17-amino acid p300/CBP and ETO target motif within AD1 activation domains of E proteins. In leukemic cells with a t(8;21) translocation, very stable interactions between AML1/ETO and E proteins underlie a t(8;21) translocation-specific silencing of E protein function through an aberrant cofactor exchange mechanism. Zhang et al. (2004) concluded that their studies identified E proteins as AML1/ETO targets whose dysregulation may be important for t(8;21) leukemogenesis, as well as an E protein silencing mechanism that is distinct from that associated with differentiation-inhibitory proteins.
Mulloy et al. (2005) transduced CD34 (142230)-positive cells with a retrovirus carrying the AML1-ETO fusion transcript and found that AML1-ETO expression upregulated NTRK1 (191315). Physiologic concentrations of nerve growth factor (NGF; see 162030) increased the proliferation of AML1-ETO-transduced cells. Furthermore, NGF and IL3 (147740) synergistically promoted the expansion of AML1-ETO-expressing cells, but not control CD34-positive cells, in liquid culture. Mulloy et al. (2005) examined a large number of AML bone marrow or peripheral blood samples and found that those containing the t(8;21) translocation expressed significantly higher levels of NTRK1 mRNA than samples without the translocation. They concluded that the NGF/NTRK1 signaling pathway may be involved in the development of AML.
Wang et al. (2011) found that AML1-ETO, a fusion protein generated by the t(8;21) translocation, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34+ cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Wang et al. (2011) concluded that lysine acetyltransferases represent a potential therapeutic target in AML.
Sun et al. (2013) showed that in human leukemic cells, AML1-ETO resides in and functions through a stable AML1-ETO-containing transcription factor complex (AETFC) that contains several hematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, colocalize genomewide, cooperatively regulate gene expression, and contribute to leukemogenesis. Within the AETFC complex, AML1-ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2-N2B complex revealed a unique interaction pattern in which an N2B peptide makes direct contact with side chains of 2 NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Disruption of this interaction by point mutations abrogated AML1-ETO-induced hematopoietic stem/progenitor cell self-renewal and leukemogenesis.
AML1/MDS1/EAI1 Fusion Protein
Helbling et al. (2004) found that the leukemic AML1-MDS1-EAI1 (AME) fusion protein suppressed CEBPA protein. In contrast to the AML1-ETO fusion, AME failed to suppress CEBPA mRNA expression. Helbling et al. (2004) found that a putative inhibitor of CEBPA translation, calreticulin (CRT; 109091), was strongly activated after induction of AME in a cell line experimental system (14.8-fold) and in AME patient samples (12.2-fold). Moreover, inhibition of CRT by small interfering RNA restored CEBPA levels. These results identified CEBPA as a key target of the leukemic fusion protein AME and suggested that modulation of CEBPA by CRT may represent a mechanism involved in the differentiation block in AME leukemias.
AML1/FOG2 Fusion Protein
Chan et al. (2005) analyzed a t(X;21)(p22.3;q22.1) translocation in a patient with myelodysplasia that fused AML1 in-frame to the FOG2 (ZFPM; 603693) gene. The reciprocal gene fusions were both expressed in bone marrow. AML1-FOG2, which fused the DNA-binding domain of AML1 to most of FOG2, repressed the transcriptional activity of both core-binding factor and GATA1 (305371). AML1-FOG2 retains a motif that recruits the corepressor C-terminal-binding protein (CTBP; see 602619) and these proteins associate in a protein complex.
AML1/TEL Fusion Protein
Hong et al. (2008) explored the clonal evolution of a form of childhood precursor-B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL-AML1 fusion gene. They identified a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one preleukemic and one with frank leukemia, Hong et al. (2008) established the lineage-derived relationship between these cancer-propagating cells and the preleukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1-transduced cord blood cells suggested that TEL-AML1 functions as a first-hit mutation by endowing this preleukemic cell with altered self-renewal and survival properties.
Miyoshi et al. (1995) determined that the RUNX1 gene contains 9 exons and spans more than 150 kb. The Runt domain is encoded by part of exon 3, exon 4, and exon 5. Promoter regions are found in exon 1 and exon 3.
Levanon et al. (2001) determined that the RUNX1 gene contains 12 alternatively spliced exons and spans 260 kb. It has 2 distinct 5-prime UTRs (UTR1 and UTR2) separated by 160 kb, both of which contain functional promoter regions. Levanon et al. (2001) determined that UTR1 mediates cap-dependent translation, while UTR2 has an internal ribosomal entry site (IRES) and mediates cap-independent translation. The 300 kb encompassing the RUNX1 gene includes 22 CpG-rich regions that are at least 200 bp long. There are 2 CpG islands near the proximal promoter (P2), but none near the distal promoter (P1). The longest CpG island (3.67 kb), which overlaps the beginning of the terminal exon, is among the largest human CpG islands known. The RUNX1 gene is relatively poor in repetitive sequences, but Alu repeats are uniformly distributed throughout the gene. A 555-bp region, which follows the final Runt domain-encoding exon and lies near a common t(8;21) breakpoint, shares a high degree of identity with an intronic region of the FLI1 gene (193067), which is located on chromosome 11. Levanon et al. (2001) concluded that a portion of the FLI1 gene was 'imported' into RUNX1 by a transposition event 25 to 35 Myr ago.
Avramopoulos et al. (1992) detected a polymorphism in the 3-prime untranslated region of the AML1 gene and used it in a genotyping of CEPH families to narrow the assignment to 21q22.3, between markers D21S216 and D21S211. By fluorescence in situ hybridization, Levanon et al. (1994) confirmed the assignment of AML1 to 21q22. AML1 is transcribed from telomere to centromere (Miyoshi et al., 1991).
Levanon et al. (2001) noted that the position of the RUNX1 gene at chromosomal band 21q22.12 marks the transition between a telomeric gene-poor region and a centromeric gene-rich region.
Rowley (1990) estimated that 18% of patients of the AML M2 subtype have the t(8;21)(q22;q22) rearrangement, and Johansson et al. (1991) found the t(8;21) in 18% of AML-M2 cases with a remarkable geographic variation. Miyoshi et al. (1991) determined that the t(8;21) breakpoints were clustered within a limited region of the AML1 gene, probably within the same intron. The chimeric gene in the 8;21 translocation contains the 5-prime region of AML1, including the segment homologous to 'runt,' a segmentation gene of Drosophila, fused to the 3-prime region of ETO (Erickson et al., 1992).
The involvement of the AML1 gene in oncogenic transformation is noteworthy since children with trisomy 21 have an increased risk of leukemia. In addition, Down syndrome neonates sometimes have a transient myeloproliferative disorder or transient leukemia that mimics congenital leukemia. In about 50% of leukemic Down syndrome children, the disease is of the acute megakaryoblastic leukemia (AMKL-M7) type (Zipursky et al., 1992). This type of leukemia, which is relatively rare among children, is estimated to be 400 times as common in Down syndrome as in other children.
Nucifora et al. (1994) consistently found fusion transcripts between AML1 and EAP (RPL22; 180474) or between AML1 and previously unidentified sequences that they named MDS1 (600049), for 'MDS-associated sequences,' in the leukemic cells of 4 patients with therapy-related myelodysplasia/acute myeloid leukemia and in 1 patient with chronic myelogenous leukemia in blast crisis, all of whom had a t(3;21). In addition, they identified a third chimeric transcript, AML1/EVI1 (165215), in 1 of the therapy-related acute myeloid leukemia patients. Pulsed field gel electrophoresis established the order of the genes as EAP, the most telomeric, and EVI1, the most centromeric, with MDS1 situated between them. The results indicated that translocations can involve multiple genes and affect gene expression over long distances.
Nucifora and Rowley (1995) reviewed the involvement of the AML1 gene in the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Three loci closely situated to each other on 3q26 are involved in fusions with AML1 in the 3;21 translocations: EVI1, EAP, and MDS1. They pointed out that the order of the genes on 3q26 is TEL--EAP--MDS1--EVI1 and provided a diagram of the 3q26 region containing these genes and of the various chimeric junctions they had isolated from t(3;21) patients.
Okuda et al. (1996) reviewed the literature on AML1 and its role in multiple chromosomal translocations in human leukemia. The AML1-ETO chimeric product resulting from t(8;21) occurs in approximately 15% of cases of acute myeloid leukemia. An inversion of chromosome 16 (inv16) occurs in 15 to 18% of cases of de novo AML and results in the fusion of CBFB to a smooth muscle myosin heavy chain gene, MYH11 (160745), and produces a chimeric product that retains its ability to interact with AML1. In t(3;21) translocations in rare cases of myelodysplasia and blast transformation of chronic myelogenous leukemia, AML1 is fused with either the EVI1 gene (165215), which encodes a known zinc finger-containing transcription factor, or either of 2 alternative genes of unknown function, EAP and MDS1, which are located adjacent to EVI1 on 3q26. Although these findings might suggest that AML1 alterations are limited to leukemia of myeloid lineage, Pui (1995) demonstrated AML1 is frequently mutated in pediatric B progenitor acute lymphoblastic leukemia (ALL), the most common malignancy seen in children. Cloning of the ALL-associated t(12;21) revealed the formation of a chimeric gene that encoded a fusion protein consisting of the N-terminal helix-loop-helix domain of TEL (600618), a member of the Ets-like family of transcription factors, fused with a nearly complete AML1 protein. Analysis of a large number of pediatric ALL cases demonstrated expression of the TEL-AML1 chimeric transcript in approximately 25% of cases with a B progenitor immunophenotype, despite the complete lack of cytogenetic evidence of this translocation in the majority of cases.
Uechi et al. (2001) reported that the RPL22 gene, or EAP, maps to chromosome 1p36.3, not chromosome 3q26. They concluded that the chromosomal breakage on 3q26 described by Nucifora et al. (1994), Nucifora and Rowley (1995), and Okuda et al. (1996) occurred in a processed RPL22 pseudogene, directing production of a fusion transcript.
The t(16;21)(q24;q22) translocation is a rare but recurrent chromosomal abnormality associated with therapy-related myeloid malignancies. Gamou et al. (1998) reported that the AML1 gene was fused to MTG16 (603870) in 4 patients with the t(16;21)(q24;q22) translocation. As in t(8;21), the t(16;21) breakpoints occurred between exons 5 and 6 of AML1 and between exons 1 and 2 or exons 3 and 4 of MTG16. While the AML1-MTG16 chimeric transcript was present in all 4 t(16;21) patients tested, the reciprocal MTG16-AML1 mRNA was present in only 1 patient and its predicted product was truncated, suggesting that AML1-MTG16 rather than MTG16-AML1 is involved in the pathogenesis of t(16;21) leukemia.
In a review of oncogenic transcription factors in human acute leukemias, Look (1997) diagrammed the distribution of translocation-generated oncogenes among the acute leukemias of children and young adults. The most frequent translocation causing ALL was t(12;21), leading to the TEL-AML1 oncogene and accounting for 20% of ALL cases. The t(8;21)-generated AML1-ETO oncogene (133435) accounted for 12% of AML cases (a myeloblastic endtype).
Look (1997) diagrammed 2 distinct mechanisms by which chromosomal translocations aberrantly activate genes encoding transcription factors, such as CBFA2. Transcription factor protooncogenes that are silent or expressed at lower levels in the progenitor cells of a particular lineage may be activated when placed under the control of potent enhancer elements within the regulatory region of a gene that is normally highly expressed. Typically, the regulatory region in these cases is contributed by one of the immunoglobulin or T-cell receptor genes present in lymphoid precursors of either the B or T lineage. More commonly, chromosomal breakpoints occur within introns, between the coding sequences of each of 2 transcription factor genes on different chromosomes, producing a fusion gene that encodes a chimeric transcription factor with altered function. The regulatory sequences that drive expression of the hybrid gene generally derive from the gene that contributes the amino-terminal amino acids to the chimeric protein; the carboxy-terminal amino acids often derive from a gene that is not normally expressed in the progenitor cells in which the chimeric oncoprotein arises.
Mikhail et al. (2002) stated that 14 different chromosomal translocations had been described in human leukemias in which AML1 was involved. They described a novel chromosomal translocation, t(4;21)(q31;q22), that disrupted the AML1 gene in a 12-year-old boy with newly diagnosed T-cell ALL. This was said to have been the first reported chromosomal translocation where AML1 was rearranged in childhood T-cell ALL. Candidate partner genes at chromosome 4q31 included interleukin-15 (IL15; 600554) and high-mobility group protein-2 (HMGB2; 163906).
Specchia et al. (2004) described 6 insertion events among 82 (73%) AML cases characterized by the RUNX1/CBFA2T1 fusion gene. Of these insertion events, 1 showed ins(8;21) and 5 showed ins(21:8). Specchia et al. (2004) determined that insertions generating the fusion gene showed variable breakpoints, and the size of the inserted elements ranged from 2.4 to 44 Mb. They concluded that the rearrangement does not seem to associate with a subset of patients with common prognostic features, the insertions are not linked to the presence of other cytogenetic rearrangements, and the crucial role of the RUNX1/CBFA2T1 fusion gene in leukemogenesis does not appear to depend on the breakpoint location or the insertion size.
Chan et al. (2005) described a t(X;21)(p22.3;q22.1) translocation in a patient with myelodysplasia that fused AML1 in-frame to FOG2. Chan et al. (2005) anticipated that the partner gene would be located on the X chromosome, but by FISH, they showed that the FOG2 gene had been translocated from chromosome 8 to the X chromosome, indicating a complex chromosomal rearrangement.
In 3 patients with acute myeloid leukemia with reciprocal 21q22/RUNX1 translocations involving chromosomes 1 and 4, Nguyen et al. (2006) identified 3 novel RUNX1 translocation partner genes: ZNF687 (610568), on 1q21.2; YTHDF2 (610640), on 1p35; and SH3D19 (608674), on 4q31.1. The translocation events occurred between exons 3 and 7 of the RUNX1 gene. The partner gene breakpoints localized to the regions in the partner genes with the highest Alu density, suggesting that Alus may have contributed to the recombination events.
Familial Platelet Disorder with Associated Myeloid Malignancy
Familial platelet disorder with associated myeloid malignancy (FPDMM; 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukemia. Informative recombination events in 6 pedigrees with this disorder showed evidence of linkage to markers on 21q and identified an 880-kb interval containing the disease gene. By mutation analysis of regional candidate genes, Song et al. (1999) demonstrated nonsense mutations or intragenic deletion of one allele of the CBFA2 gene that cosegregated with the disease in 4 of the pedigrees. In the other 2 pedigrees, heterozygous CBFA2 missense mutations were found that cosegregated with the disease and involved phylogenetically conserved amino acids R166 and R201 (151385.0002), respectively. Analysis of bone marrow or peripheral blood cells from affected individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. The findings supported a model of familial platelet disorder in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukemia.
In 3 families with the autosomal dominant familial platelet disorder characterized by thrombocytopenia and a propensity to develop AML, Michaud et al. (2002) found linkage to 21q22.1 and 3 novel heterozygous point mutations in the RUNX1 gene: lys83 to glu (K83E; 151385.0003), IVS4+3delA (151385.0004), and tyr260 to ter (Y260X; 151385.0005). They performed functional investigations of the 7 runt domain point mutations of RUNX1 in this disorder that had been reported to that time. Consistent with the position of the mutations at the RUNX1-DNA interface, DNA binding of all mutant RUNX1 proteins was absent or significantly decreased. They discussed the hypothesis that a second mutation has to occur, either in RUNX1 or another gene, to cause leukemia among individuals harboring RUNX1 FPD/AML mutations. Propensity to acquire these additional mutations may be determined, at least partially, by the initial RUNX1 mutation.
Preudhomme et al. (2009) reported 16 patients from 4 unrelated French families with familial platelet disorder associated with heterozygous mutation in or deletion of the RUNX1 gene (see, e.g., 151385.0010). Ten patients progressed to acute leukemia, including 7 with AML, 1 with T-cell ALL, 1 with T-cell ALL followed by AML, and 1 with an uncharacterized form of leukemia. Among 8 patients with AML studied in detail, 6 were found to have a somatic RUNX1 mutation: 4 had acquired point mutations and 2 had acquired trisomy 21. The findings indicated that a second genetic event involving RUNX1 is often associated with progression to acute leukemia in patients with familial platelet disorder.
Lee et al. (2023) transfected CD34+ stem cells with a lentivirus containing a short hairpin RNA (shRNA) targeted against RUNX1. The transfected cells had decreased terminal megakaryocyte differentiation and decreased responsiveness to the megakaryocyte agonists TRAP (190440) and convulxin. Lee et al. (2023) concluded that multiple receptor pathways were deficient in the RUNX1-deficient megakaryocytes. Treatment with RepSox, a small molecule that blocks the transforming growth factor beta-1 (TGFB1; 190180) pathway, improved megakaryocyte differentiation.
Acute Myeloblastic Leukemia
Using RT-PCR and a nonisotopic RNase cleavage assay, Osato et al. (1999) detected somatic point mutations in the Runt domain of the AML1 gene in 8 of 160 patients with acute myeloblastic leukemia. Functional analysis indicated that those with missense mutations showed neither DNA binding nor transactivation. Immunofluorescence microscopy demonstrated that nonsense mutations resulted in the loss of these functions and also led to weakened nuclear and increased cytoplasmic expression.
Taketani et al. (2002) screened the RUNX1 gene in 46 Down syndrome patients with hematologic malignancies. They identified a heterozygous missense mutation (H58N; 151385.0008) in 1 patient diagnosed with transient myeloproliferative disorder (see 190685) 5 days after birth. The patient died suddenly 12 months after birth; it was not known whether she developed acute myeloid leukemia.
Osato (2004) reviewed the role of RUNX1 point mutations in leukemia development. They pointed out that sporadic point mutations of the RUNX1 gene are found frequently in 3 leukemia entities: AML M0 subtype, myelodysplastic syndrome (MDS)-AML, and secondary (therapy-related) MDS/AML. Half of the point mutations in M0 cases are biallelic, although the frequency varies with ethnicity. Most of the RUNX1 mutations are clustered in the Runt domain and result in defective binding but active beta subunit binding, which is consistent with 3-dimensional structural findings and may explain the dominant inhibitory effects. Unlike the classical tumor suppressor genes requiring biallelic inactivation, haploinsufficient RUNX1 is apparently leukemogenic. However, RUNX1 abnormalities per se are insufficient to cause full-blown leukemia.
The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The Cancer Genome Atlas Research Network (2013) identified recurrent mutations in the RUNX1 gene in 19/200 (10%) samples.
Brewin et al. (2013) noted that the study of the Cancer Genome Atlas Research Network (2013) did not reveal which mutations occurred in the founding clone, as would be expected for an initiator of disease, and which occurred in minor clones, which subsequently drive disease. Miller et al. (2013) responded that genes mutated almost exclusively in founding clones in their study included RUNX1 (9 of 9 mutations in founding clones). They identified several other genes that contained mutations they considered probable initiators, and other genes mutations in which were considered probably cooperating mutations.
Somatic Mutations in Breast Cancer
To correlate the variable clinical features of estrogen-receptor-positive breast cancer (see 114480) with somatic alterations, Ellis et al. (2012) studied pretreatment tumor biopsies accrued from patients in 2 studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including 5 genes (RUNX1; CBFB, 121360; MYH9, 160775; MLL3, 606833; and SF3B1, 605590) previously linked to hematopoietic disorders.
Banerji et al. (2012) reported the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA (171834), TP53 (191170), AKT1 (164730), GATA3 (131320), and MAP3K1 (600982), Banerji et al. (2012) discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1.
Monoallelic RUNX1 mutations cause familial platelet disorder with predisposition to AML. Sporadic mono- and biallelic mutations are found at high frequencies in AML of the M0 type, in radiation-associated and therapy-related myelodysplastic syndrome and AML, in isolated cases of AML relapse, and in chronic myelogenous leukemia in blast phase. Mutations in RUNX2 (600211) cause cleidocranial dysplasia (CCD; 119600). Most hematopoietic missense mutations in RUNX1 involve DNA-contacting residues in the Runt domain, whereas most CCD mutations in RUNX2 are predicted to impair binding of core-binding factor, beta subunit (CBFB; 121360) or the Runt domain structure. Matheny et al. (2007) introduced different classes of missense mutations into RUNX1 and characterized their effects on DNA and CBF-beta binding by the Runt domain, and on RUNX1 function in vivo. Mutations involving DNA-contacting residues severely inactivated RUNX1 function, whereas mutations that affected CBF-beta binding but not DNA binding resulted in hypomorphic alleles. Matheny et al. (2007) concluded that whereas hypomorphic RUNX2 alleles can cause CCD, hematopoietic disease requires more severely inactivating RUNX1 mutations.
To investigate the normal biologic function of AML1 in vivo, Okuda et al. (1996) generated mice carrying a disrupted AML1 allele using gene targeting in embryonic stem (ES) cells. Mice lacking AML1 died during midembryonic development, secondary to the complete absence of fetal liver-derived hematopoiesis. Moreover, homozygous AML1-deficient cells failed to contribute to hematopoiesis in chimeric animals. These findings indicated that AMl1-regulated target genes are essential for definitive hematopoiesis of all lineages. Wang et al. (1996) likewise analyzed the role of CBFA2 in mammalian development by gene disruption in mice. They found that mice lacking a CBF-alpha-2 protein capable of binding DNA died between embryonic days 11.5 and 12.5 due to hemorrhaging in the central nervous system, at the nerve/CNS interfaces of cranial and spinal nerves, and in somitic/intersomitic regions along the presumptive spinal cord. Hemorrhaging was preceded by symmetric, bilateral necrosis in these regions. Definitive erythropoiesis and myelopoiesis did not occur in Cbfa2-deficient embryos, and disruption of 1 copy of the Cbfa2 gene significantly reduced the number of progenitors for erythroid and myeloid cells.
As indicated earlier, the human t(3;21)(q26;q22) translocation is found as a secondary mutation in some cases of chronic myelogenous leukemia during blast phase and in therapy-related myelodysplasia and acute myelogenous leukemia. One result of this translocation is a fusion between the AML1, MDS1, and EVI1 genes. Cuenco et al. (2000) investigated the role of the AML1/MDS1/EVI1 fusion gene, referred to by the authors as AME, which encodes a transcription factor of approximately 200 kD, in leukemogenesis. They analyzed the effect of the AME fusion gene in vivo by expressing it in mouse bone marrow cells via retroviral transduction. They found that mice transplanted with AME-transduced bone marrow cells suffered from an acute myelogenous leukemia 5 to 13 months after transplantation. The disease could be readily transferred into secondary recipients with a much shorter latency. Morphologic analysis of peripheral blood and bone marrow smears demonstrated the presence of myeloid blast cells and differentiated but immature cells of both myelocytic and monocytic lineages. Cytochemical and flow cytometric analysis confirmed that these mice had a disease similar to the human acute myelomonocytic leukemia.
Okuda et al. (2000) created a knockin allele which expressed mouse AML1b cDNA under the control of the endogenous AML1 regulatory sequences in AML1-deficient mouse ES cells. Knockin clones restored the ability of AML1-deficient ES cells to undergo differentiation into all lineages of definitive hematopoiesis in vitro. When these ES cells were injected into blastocysts, the resultant chimeric mice were found to contain contributions from the knockin clones in all tissues, including sites of lymphohematopoiesis. In vitro rescue (transfecting a series of C-terminal deletion mutants of AML1b into AML1-deficient ES cells) revealed that the 61 C-terminal residues of AML1b, including the VWRPY motif at the C terminus which has been conserved throughout evolution among all known AML1-related molecules, are not required for definitive hematopoiesis. The authors concluded that the hematopoietic defect seen in AML1-deficient mice is due solely to the loss of transcriptionally active AML1.
Creation of the AML1/TEL fusion disrupts 1 copy of the TEL gene and 1 copy of the AML1 gene; loss of one or the other is associated with cases of acute leukemia without the presence of the AML1/TEL fusion gene. To determine if AML1/TEL can contribute to leukemogenesis, Bernardin et al. (2002) transduced marrow from C57BL/6 mice with a retroviral vector expressing AML1/TEL or with a control vector. Two of the 9 AML1/TEL mice developed ALL, whereas none of the 20 control mice developed leukemia. Bernardin et al. (2002) also used the AML1/TEL vector to transduce marrow from C57BL/6 mice lacking the overlapping p16(INK4a)p19(ARF) genes (600160) and transplanted the cells into wildtype recipients. No control mice died, but 6 of 8 AML1/TEL/p16p19 mice died with leukemia. These findings indicated that AML1/TEL contributes to leukemogenesis and may cooperate with loss of p16p19 to transform lymphoid progenitors.
Schwieger et al. (2002) introduced the AML1/ETO fusion gene into mouse bone marrow cells and transplanted these cells into wildtype mice. They found that AML1/ETO directly stimulated granulopoiesis, suppressed erythropoiesis, and impaired maturation of myeloid, B, and T lymphoid cells in vivo. By introducing AML1/ETO into bone marrow cells from Icsbp (601565)-deficient mice, Schwieger et al. (2002) showed that AML1/ETO synergized with Icsbp deficiency to induce myeloblastic transformation in bone marrow.
Tsuzuki et al. (2004) analyzed hemopoiesis in mice syngeneically transplanted with TEL/AML1-transduced bone marrow stem cells. TEL/AML1 expression was associated with an accumulation/expansion of primitive Kit (164920)-positive multipotent progenitors and a modest increase in myeloid colony-forming cells. TEL/AML1 expression was, however, permissive for myeloid differentiation. Analysis of B lymphopoiesis revealed an increase in early pro-B cells but a differentiation deficit beyond that stage, which resulted in lower B-cell production in the marrow. TEL/AML1-positive B-cell progenitors exhibited reduced expression of genes crucial for the pro-B to pre-B cell transition.
Ichikawa et al. (2004) used the Cre-loxP system to assess the requirement of AML1/Runx1 in adult hematopoiesis. In the absence of AML1, hematopoietic progenitors were fully maintained with normal myeloid cell development. However, AML1-deficient bone marrow showed inhibition of megakaryocytic maturation, increased hematopoietic progenitor cells and defective T- and B-lymphocyte development. Ichikawa et al. (2004) concluded that AML1 is required for maturation of megakaryocytes and differentiation of T and B cells, but not for the maintenance of hematopoietic stem cells in adult hematopoiesis.
Fenske et al. (2004) created mice with targeted expression of AML1/ETO to the hematopoietic stem cell compartment. Mutant mice were born in mendelian ratios with no apparent abnormalities in growth or fertility. However, mutant mice developed spontaneous myeloproliferative disorder with a latency of 6 months and a penetrance of 82% at 14 months.
RUNX1 is poorly expressed in innervated muscle, but is strongly induced in muscle shortly after denervation. To determine the function of Runx1 in skeletal muscle, Wang et al. (2005) created mice with Runx1 deletion targeted to skeletal muscle. Mutant mice were healthy and fertile and were born in expected numbers. In wildtype mice, peripheral nerve damage or limb immobilization leads to increased Runx1 expression and muscle atrophy. In Runx1-null myofibers, denervation resulted in severe atrophy, indicating a requirement for Runx1 to sustain denervated muscle and to minimize atrophy. Runx1 was also required to sustain muscle by preventing denervated myofibers from undergoing myofibrillar disorganization and autophagy. Wang et al. (2005) found that 29 genes, encoding channels, signaling molecules, and structural proteins, but not transcription factors, were misexpressed in denervated Runx1 mutant muscle.
Robin et al. (2006) noted that Runx1 -/- mice die at embryonic day 12 to 13 with no aorta-gonad-mesonephros (AGM) region and fetal liver hematopoiesis, and that Runx1 +/- mice have reduced adult-repopulating ability of hematopoietic stem cells (HSCs). Since IL3 is a RUNX1 target, they examined whether Il3 affects HSCs in the mouse embryo. Using limiting dilution and Poisson statistical analysis, Robin et al. (2006) found that Runx1 +/- mice had fewer HSCs in AGM, but not in yolk sac or placenta, than wildtype mice. AGM-derived HSCs cultured from Runx1 +/- mice in the presence of Il3, but not other cytokines, followed by transplantation, rescued the HSCs in a dose-dependent manner. In situ hybridization and flow cytometric analysis showed that expression of Il3 was strong in wildtype embryos, but it was reduced in Runx1 +/- embryos and absent in Runx1 -/- embryos. RT-PCR and FACS analyses demonstrated expression of all mouse Il3 receptor chains (see IL3RA; 308385) in HSCs of both wildtype and Runx1 +/- mice. Transplantation experiments showed that Il3 neutralizing antibody or deletion of Il3 prevented growth of normal HSC numbers. Robin et al. (2006) proposed that IL3 acts as a survival and proliferation factor for preexisting HSCs and is critical for HSC fate determination and expansion in the embryo.
To test the hypothesis that inactivation of 1 Runx1 allele could reveal the capacity of the yolk sac to generate the hematopoietic stem cell lineage, Samokhvalov et al. (2007) designed a noninvasive pulse-labeling system based on Cre/loxP recombination. They showed that in Runx1 +/- mice, yolk sac cells expressing Runx1 at embryonic day 7.5 developed into fetal lymphoid progenitors and adult hematopoietic stem cells. During midgestation the labeled (embryonic day 7.5) yolk sac cells colonized the umbilical cord, the aorta-gonad-mesonephros region, and subsequently the embryonic liver. This raised the possibility that some hematopoietic stem cells associated with major embryonic vasculature are derived from yolk sac precursors. Samokhvalov et al. (2007) observed virtually no contribution of the labeled cells towards the yolk sac vasculature, indicating early segregation of endothelial and hematopoietic lineages.
Dowdy et al. (2010) created a Runx1 knockin mouse with a C-terminal truncation (Q307X), which models mutations observed in patients with leukemia and myeloproliferative disorders. The homozygote knockin mouse exhibited embryonic lethality at embryonic day 12.5 due to central nervous system hemorrhages and a complete lack of hematopoietic stem cell function. While able to bind DNA, the mutant protein was unable to activate target genes, resulting in deregulation of various hematopoietic markers. The authors concluded that the subnuclear targeting and transcriptional regulatory activities of the Runx1 C-terminus are critical for hematopoietic development, and that compromising the C-terminal functions of Runx1 is responsible for the pathologic consequences of several somatic mutations and Runx1-related leukemic fusion proteins observed in human patients.
Lee et al. (2023) infused megakaryocytes that were transfected with a lentivirus containing a shRNA targeted against RUNX1 into NOD scid gamma (NSG) mice. The treated mice had impaired platelet activation and impaired thrombus formation. When the megakaryocytes that were transfected with a lentivirus containing a shRNA were treated with RepSox (a small molecule that blocks the TGFB1 pathway) prior to infusion into the mice, the platelet agonist response was partially restored and bleeding time was normalized.
Lee et al. (2023) performed hematopoetic stem cell transplantation with mixed populations of RUNX1 heterozygous mutant and RUNX1 wildtype stem cells into 2 rhesus macaque monkeys. The RUNX1 mutant cells expanded over time compared to cells that had wildtype RUNX1, and platelet counts and platelet differentiation remained abnormal over time. Lee et al. (2023) concluded that heterozygosity for a RUNX1 mutation did not cause a competitive disadvantage in hematopoietic stem cells.
In a family with familial platelet disorder (FPDMM; 601399) in 3 generations, Song et al. (1999) demonstrated that affected individuals had a heterozygous G-to-T transversion in the splice acceptor site in the last nucleotide of intron 3. The change enforced the use of a cryptic splice acceptor in exon 4 with a resultant frameshift causing a stop codon.
In a family with familial platelet disorder with acute myelogenous leukemia (FPDMM; 601399) in 3 generations, Song et al. (1999) found a heterozygous arg201-to-gln (R201Q) missense mutation in the CBFA2 gene.
In a family with typical features of familial platelet disorder with predisposition to acute myelogenous leukemia (FPDMM; 601399), Michaud et al. (2002) found a heterozygous A-to-G transition in exon 3 of the RUNX1 gene resulting in a lys83-to-glu substitution (K83E).
In a family with typical features of familial platelet disorder with predisposition to acute myelogenous leukemia (FPDMM; 601399), Michaud et al. (2002) found a 1-bp deletion in the splice donor site of intron 4 of the RUNX1 gene (IVS4+3delA). The novel transcript resulting from use of a cryptic donor site resulted in frameshift after amino acid 135, addition of 41 unrelated residues, and termination at codon 177 (Arg135fsTer177).
In a family with typical features of familial platelet disorder with predisposition to acute myelogenous leukemia (FPDMM; 601399), Michaud et al. (2002) found a heterozygous C-to-A transversion in exon 7B of the RUNX1 gene, resulting in atyr260-to-ter (Y260X) substitution.
Walker et al. (2002) identified heterozygosity for an ala107-to-pro (A107P) mutation in the RUNX1 gene in members of a family with autosomal dominant inheritance of thrombocytopenia with propensity to acute myeloid leukemia (FPDMM; 601399). Individuals with thrombocytopenia bruised easily, to a degree that was out of keeping with the platelet count. Studies of platelet function revealed an 'aspirin-like' platelet function abnormality. The pedigree was identified through a proband who developed acute myeloid leukemia at 31 years of age, 4 years after thrombocytopenia was first noted.
Taketani et al. (2002) screened the RUNX1 gene in 46 Down syndrome patients with hematologic malignancies. They identified a heterozygous C-to-A transversion in codon 58, resulting in a his58-to-asn mutation (H58N), in 1 patient diagnosed with transient myeloproliferative disorder (see 190685) 5 days after birth. The patient died suddenly 12 months after birth; it was not known whether she developed acute myeloid leukemia. The mutation had previously been reported in an adult patient with acute myeloid leukemia of the M0 subtype (601626) by Osato et al. (1999), who determined that the H58N mutant has nearly normal function.
In a boy with autosomal dominant platelet disorder and myeloid malignancy (FPDMM; 601399), Beri-Dexheimer et al. (2008) identified a heterozygous 8-bp deletion in exon 4 of the RUNX1 gene, most likely resulting in premature termination and nonsense-mediated decay of mRNA. His mother, who did not have a history of bleeding but showed abnormal platelet function, also carried the mutation. Only the boy developed AML.
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