RUNX1T1

Summary

RUNX1T1 (RUNX1 partner transcriptional co-repressor 1, HGNC:1535) is a protein-coding gene on chromosome 8q21.3, encoding Protein CBFA2T1 (Q06455). Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes.

This gene encodes a member of the myeloid translocation gene family which interact with DNA-bound transcription factors and recruit a range of corepressors to facilitate transcriptional repression. The t(8;21)(q22;q22) translocation is one of the most frequent karyotypic abnormalities in acute myeloid leukemia. The translocation produces a chimeric gene made up of the 5’-region of the runt-related transcription factor 1 gene fused to the 3’-region of this gene. The chimeric protein is thought to associate with the nuclear corepressor/histone deacetylase complex to block hematopoietic differentiation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 862 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 18
• Clinical variants (ClinVar): 107 total — 1 pathogenic, 1 likely-pathogenic
• Cancer driver (intOGen): activating (oncogene-like) across 6 cancer types
• MANE Select transcript: NM_175634

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1535
Approved symbol	RUNX1T1
Name	RUNX1 partner transcriptional co-repressor 1
Location	8q21.3
Locus type	gene with protein product
Status	Approved
Aliases	CDR, ETO, MTG8, ZMYND2
Ensembl gene	ENSG00000079102
Ensembl biotype	protein_coding
OMIM	133435
Entrez	862

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 30 protein_coding, 8 protein_coding_CDS_not_defined, 8 nonsense_mediated_decay, 3 retained_intron

ENST00000360348, ENST00000396218, ENST00000422361, ENST00000436581, ENST00000517493, ENST00000517792, ENST00000517919, ENST00000518256, ENST00000518317, ENST00000518361, ENST00000518449, ENST00000518823, ENST00000518832, ENST00000518844, ENST00000518954, ENST00000518992, ENST00000519061, ENST00000519422, ENST00000519577, ENST00000519847, ENST00000520047, ENST00000520172, ENST00000520428, ENST00000520556, ENST00000520583, ENST00000520724, ENST00000520974, ENST00000520978, ENST00000521054, ENST00000521078, ENST00000521319, ENST00000521375, ENST00000521553, ENST00000521733, ENST00000521751, ENST00000521897, ENST00000521902, ENST00000522065, ENST00000522163, ENST00000522316, ENST00000522467, ENST00000522860, ENST00000523168, ENST00000523290, ENST00000523629, ENST00000524215, ENST00000898140, ENST00000930694, ENST00000946002

RefSeq mRNA: 16 — MANE Select: NM_175634 NM_001198625, NM_001198626, NM_001198627, NM_001198628, NM_001198629, NM_001198630, NM_001198631, NM_001198632, NM_001198633, NM_001198634, NM_001198679, NM_001395209, NM_004349, NM_175634, NM_175635, NM_175636

CCDS: CCDS47891, CCDS56544, CCDS6256, CCDS6257, CCDS75766, CCDS75767

Canonical transcript exons

ENST00000523629 — 12 exons

Exon	Start	End
ENSE00001682869	92011002	92011091
ENSE00001706185	92005116	92005297
ENSE00002106895	92102857	92103385
ENSE00002133626	91954972	91960517
ENSE00003471634	92075965	92076137
ENSE00003490917	91975905	91975973
ENSE00003518720	91986124	91986325
ENSE00003614817	92017226	92017363
ENSE00003643194	91986887	91986972
ENSE00003673339	91991639	91991889
ENSE00003673886	91970658	91970848
ENSE00003784460	92014579	92014820

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.8242 / max 692.9967, expressed in 916 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93935	1.2682	322
93932	1.2274	429
93943	0.9066	380
93949	0.7805	406
93933	0.7592	328
93938	0.3954	96
93948	0.3867	227
93947	0.3692	169
93945	0.3218	137
93944	0.2502	103

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.86	gold quality
oocyte	CL:0000023	96.98	gold quality
sural nerve	UBERON:0015488	96.69	gold quality
buccal mucosa cell	CL:0002336	96.51	gold quality
tendon of biceps brachii	UBERON:0008188	95.41	gold quality
cortical plate	UBERON:0005343	95.38	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.36	gold quality
calcaneal tendon	UBERON:0003701	93.98	gold quality
paraflocculus	UBERON:0005351	93.96	gold quality
tendon	UBERON:0000043	93.48	gold quality
middle temporal gyrus	UBERON:0002771	93.36	gold quality
colonic epithelium	UBERON:0000397	93.26	gold quality
parietal pleura	UBERON:0002400	92.04	gold quality
nipple	UBERON:0002030	91.38	gold quality
pleura	UBERON:0000977	91.03	gold quality
endothelial cell	CL:0000115	90.83	gold quality
cerebellar vermis	UBERON:0004720	90.60	gold quality
skin of hip	UBERON:0001554	90.36	gold quality
mammary duct	UBERON:0001765	90.19	gold quality
visceral pleura	UBERON:0002401	90.16	gold quality
cerebellum	UBERON:0002037	90.01	gold quality
epithelium of mammary gland	UBERON:0003244	89.67	gold quality
entorhinal cortex	UBERON:0002728	89.24	gold quality
cerebellar cortex	UBERON:0002129	89.22	gold quality
cerebellar hemisphere	UBERON:0002245	89.06	gold quality
layer of synovial tissue	UBERON:0007616	89.04	gold quality
germinal epithelium of ovary	UBERON:0001304	88.77	gold quality
dorsal root ganglion	UBERON:0000044	88.74	gold quality
cauda epididymis	UBERON:0004360	88.61	gold quality
blood vessel layer	UBERON:0004797	88.42	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	1171.18
E-MTAB-8894	yes	1022.62
E-GEOD-93593	yes	662.67
E-MTAB-10485	yes	542.44
E-MTAB-9154	yes	474.83
E-GEOD-83139	yes	438.18
E-HCAD-5	yes	52.14
E-MTAB-7316	yes	34.13
E-CURD-119	yes	9.81
E-MTAB-5061	yes	8.64
E-CURD-112	yes	5.78
E-MTAB-6678	yes	4.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
IL3	Unknown

Upstream regulators (CollecTRI, top): CTNNBL1, DNMT1, ETS1, GATA1, GFI1, GFI1B, HIF1A, NCOR1, NCOR2, RUNX1, SMAD4, ZBTB16

miRNA regulators (miRDB)

211 targeting RUNX1T1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-568	99.98	69.86	2084

Literature-anchored findings (GeneRIF, showing 40)

• no conclusive evidence as yet that the AML1/ETO chimeric gene is sufficient per se to induce leukemia. (PMID:11869944)
• Analysis of nuclear distribution of the AML1/ETO protein and its homology domains led to identification of domains in ETO responsible for intranuclear transport and subnuclear distribution of AML1/ETO. (PMID:11983111)
• Potential involvement of the AML1-MTG8 fusion protein in the granulocytic maturation characteristic of the t(8;21) acute myelogenous leukemia cell (PMID:11986950)
• data demonstrate the capacity of AML1-ETO to promote the self-renewal of human hematopoietic cells and therefore support a causal role for t(8;21) translocations in leukemogenesis (PMID:12393523)
• 2 independent subnuclear targeting signals in the N- and C-terminal regions of ETO direct ETO to the same binding sites occupied by AML1ETO. This provides a molecular basis for aberrant subnuclear targeting of AML1ETO, the defect in t(8;21)-related AML. (PMID:12427969)
• ETO rearrangements leading to the AML1-ETO fusion gene are frequently the result of small hidden interstitial insertions. (PMID:12557226)
• In t(8;21) leukaemic cells expressing the aberrant fusion protein AML1-ETO, we demonstrate that this protein is part of a transcription factor complex binding to extended sequences of the c-FMS intronic regulatory region rather than the promoter. (PMID:12773394)
• Data identify ETO as a partner for Gfi-1 and Gfi-1B, and suggest that Gfi-1 proteins repress transcription through recruitment of histone deacetylase-containing complexes. (PMID:12874834)
• ETO is a bona fide corepressor that links the transcriptional pathogenesis of acute leukemias and B-cell lymphomas and offers a compelling target for transcriptional therapy of hematologic malignancies. (PMID:14551142)
• RT-PCR for the detection of AML1/ETO in children with acute non-lymphoid leukemia (ANLL) was quick, convenient and sensitive, and could be regarded as a useful method for the diagnosis and prognosis of ANLL. (PMID:14751048)
• Present in acute myeloid leukemia of M2 subtype. (PMID:15203865)
• cloning, expression, purification and crystallization of NHR3 domain (PMID:15295650)
• These findings suggest a central role of RUNX1-CBFA2T1 in the maintenance of the leukaemia. (PMID:15298716)
• study identifes E proteins as AML1-ETO targets whose dysregulation may be important for t(8;21) leukemogenesis (PMID:15333839)
• N-CoR utilizes repression domains I and III for interaction and co-repression with ETO (PMID:15377655)
• DiffeRential expression of the ETO homologues suggests that they may have a potential role in hematopoietic differentiation. (PMID:15676213)
• Alternative splicing in the AML1-MTG8 fusion gene occurs in leukemia cell lines as well as in cells of leukemia paatients with a(8;21) translocation. (PMID:15723339)
• Results suggest a novel mechanism for gene silencing mediated by RUNX1/MTG8 and support the combination of HDAC and DNMT inhibitors as a novel therapeutic approach for t(8;21) AML. (PMID:15735013)
• AML1 and ETO are fused together at the t8;21 translocation breakpoint, resulting in the expression of a chimeric protein called AML1-ETO, which acts as a constitutive transcriptional repressor. (PMID:15829516)
• Translocations in acute myeloid leukemia (AML) is the t(8;21) is characterized by AML1-MTG8 (ETO) mutation. (PMID:16502583)
• Oligomerization is also required for AML1/ETO’s interactions with ETO, MTGR1, and MTG16, but not with other corepressor molecules. (PMID:16616331)
• Suppression of AML1/MTG8 results in the increased expression of genes associated with myeloid differentiation, such as AZU1, BPI, CTSG, LYZ and RNASE2 as well as of antiproliferative genes such as IGFBP7, MS4A3 and SLA both in blasts and in cell lines (PMID:16652140)
• Conditional expression of AML1-ETO by the ecdysone-inducible system dramatically increases the expression of connexin 43 together with growth arrest at G1 phase in leukemic U937 cells. (PMID:16741927)
• AML1T1, an alternatively spliced isoform of the t(8;21) transcript, promotes leukemogenesis. (PMID:16892037)
• The leukemia-associated fusion protein AML1-ETO could aberrantly transactivate the EEN gene through an AML1 binding site. (PMID:16990610)
• As a result, we identified 14 unique proteins deregulated in AML1-ETO-carrying leukemic cells, including 3 up-regulated such as hairy and enhancer of split 5 (HES5) and 11 down-regulated such as MAT1 (menage a trois-1. (PMID:17058450)
• AML1/ETO participates in a protein complex with the RA receptor alpha (RARalpha) at RA regulatory regions on RARbeta2. (PMID:17244680)
• Loss of p21(WAF1) facilitates AML1-ETO-induced leukemogenesis. (PMID:17284535)
• Presence of AML1-ETO fusion protein increases the susceptibility of cells to chemical carcinogens, which favors the development of additional genetic alterations. (PMID:17560011)
• AML1-ETO and JAK2 may have a role in leukemogenesis, as shown by a myeloproliferative syndrome progressing to acute myeloid leukemia [case report] (PMID:17625612)
• Isoform AML1/ETO9a was correlated to acute myeloid leukemia-M2 subtype. (PMID:17649722)
• Our study suggests that KIT activating mutations in AML with t(8; 21) are associated with diminished CD 19 and positive CD56 expression on leukemic blasts and, thus, can be phenotypically distinguished from AML1-ETO leukemias (PMID:17875504)
• constitutively and overexpressed AML1-ETO protein was cleaved to four fragments of 70, 49, 40 and 25 kDa by activated caspase-3 during apoptosis induction by extrinsic mitochondrial and death receptor signaling pathways. (PMID:17989718)
• miR-223 is a direct transcriptional target of AML1/ETO (PMID:17996649)
• MTG8/ETO and Mtg16 (ETO2) associated with TCF4 (PMID:18039847)
• These results demonstrate that scl is an important mediator of the ability of AML1-ETO to reprogram hematopoietic cell fate decisions, suggesting that scl may be an important contributor to AML1-ETO-associated leukemia. (PMID:18156164)
• VP-16 causes the ETO gene repositioning which allows AML1 and ETO genes to be localized in the same nuclear layer; data corroborate the so called “breakage first” model of the origins of recurrent reciprocal translocation (PMID:18183572)
• The interaction between SIN3B and ETO required an intact amino-terminus of ETO and the NHR2 domain. (PMID:18205948)
• Knockdown of TLE1 or TLE4 levels increased the rate of cell division of the AML1-ETO-expressing Kasumi-1 cell line, whereas forced expression of either TLE1 or TLE4 caused apoptosis and cell death. (PMID:18258796)
• In functional assays, corepressor ETO, but not AML1/ETO, augments SHARP-mediated repression in an histone deacetylase-dependent manner. (PMID:18332109)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	runx1t1	ENSDARG00000003680
mus_musculus	Runx1t1	ENSMUSG00000006586
rattus_norvegicus	Runx1t1	ENSRNOG00000005673
drosophila_melanogaster	nvy	FBGN0005636

Paralogs (2): CBFA2T2 (ENSG00000078699), CBFA2T3 (ENSG00000129993)

Protein

Protein identifiers

Protein CBFA2T1 — Q06455 (reviewed: Q06455)

Alternative names: Cyclin-D-related protein, Eight twenty one protein, Protein ETO, Protein MTG8, Zinc finger MYND domain-containing protein 2

All UniProt accessions (28): Q06455, A0A0A0MSU1, A0A1B0GX92, E5RFQ3, E5RG85, E5RH30, E5RH72, E5RHJ8, E5RI38, E5RJ32, E5RJB3, E5RJE7, E5RK76, E7EQ59, E7EQI9, E7EQJ1, E7EQW3, E7EQW7, E7ERJ9, E7ESA9, E7ESL1, E7ETA8, E7EWJ9, E7EX23, H0YBA6, H0YC25, H0YC43, W8FW32

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes. Can repress the expression of MMP7 in a ZBTB33-dependent manner. Can repress transactivation mediated by TCF12. Acts as a negative regulator of adipogenesis. The AML1-MTG8/ETO fusion protein frequently found in leukemic cells is involved in leukemogenesis and contributes to hematopoietic stem/progenitor cell self-renewal.

Subunit / interactions. Homooligomer. Homotetramerization is mediated by nervy homology region 2 (NRH2). Can interact with CBFA2T2 and CBFA2T3; heterotetramerization between members of the CBFA2T family is proposed. Interacts with TCF12, SIN3A, HDAC1, HDAC2, HDAC3, NCOR1, NCOR2. Interacts with ATN1 (via its N-terminus); the interaction enhances the transcriptional repression. Interacts (via its N-terminus) with ZBTB16; the interaction increases the transcription repression activity of ZBTB16. AML1-MTG8/ETO fusion protein interacts with CBFB. AML1-MTG8/ETO is part of a stable transcription factor complex AETFC in leukemic cells; AETFC formation seems to be involved in recruitment of EP300. AML1-MTG8/ETO nervy homology region 2-mediated oligomerization is proposed to be homotypic, required for AML1-MTG8/ETO-mediated transformation of primary hematopoietic cells and is required for AML1-MTG8/ETO interaction with TCF12.

Subcellular location. Nucleus.

Tissue specificity. Most abundantly expressed in brain. Lower levels in lung, heart, testis and ovary.

Disease relevance. A chromosomal aberration involving RUNX1T1 is frequently found in acute myeloid leukemia with maturation (AML-M2). Translocation t(8;21)(q22;q22) with RUNX1/AML1 that results in the production of AML1-MTG8/ETO fusion protein.

Domain organisation. The TAFH domain mediates interaction with transcription regulators. Nervy homology region 2 (NHR2) mediates homo- and possibly heterotypic oligomerization by forming a four-helix bundle tetrameric structure.

Similarity. Belongs to the CBFA2T family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q06455-1	MTG8B	yes
Q06455-2	MTG8A
Q06455-3	3
Q06455-4	4
Q06455-5	MTG8B-2
Q06455-6	MTG8A-2

RefSeq proteins (16): NP_001185554, NP_001185555, NP_001185556, NP_001185557, NP_001185558, NP_001185559, NP_001185560, NP_001185561, NP_001185562, NP_001185563, NP_001185608, NP_001382138, NP_004340, NP_783552, NP_783553, NP_783554 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002893	Znf_MYND	Domain
IPR003894	TAFH_NHR1	Domain
IPR013289	CBFA2T1/2/3	Family
IPR013290	CBFA2T1	Family
IPR014896	NHR2	Domain
IPR037249	TAFH/NHR1_dom_sf	Homologous_superfamily

Pfam: PF01753, PF07531, PF08788

UniProt features (81 total): mutagenesis site 22, helix 13, binding site 8, compositionally biased region 7, region of interest 7, strand 6, splice variant 5, sequence variant 3, modified residue 2, sequence conflict 2, turn 2, chain 1, domain 1, zinc finger region 1, site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
1WQ6	X-RAY DIFFRACTION	2
4JOL	X-RAY DIFFRACTION	2.91
2DJ8	SOLUTION NMR
2H7B	SOLUTION NMR
2KNH	SOLUTION NMR
2KYG	SOLUTION NMR
2OD1	SOLUTION NMR
2ODD	SOLUTION NMR
2PP4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06455-F1	64.34	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 30–31 (breakpoint for translocation to form aml1-mtg8 in aml-m2)

Ligand- & substrate-binding residues (8): 515; 518; 526; 529; 535; 539; 547; 551

Post-translational modifications (2): 41, 417

Mutagenesis-validated functional residues (22):

Position	Phenotype
125	loss of interaction with tcf12.
126	loss of interaction with tcf12.
128	loss of interaction with tcf12.
129	loss of interaction with tcf12.
129	abolishes interaction with corepressor.
136	abolishes interaction with corepressor.
170	abolishes interaction with corepressor.
173	abolishes interaction with corepressor.
175	abolishes interaction with corepressor.
177	abolishes interaction with corepressor.
178	loss of interaction with tcf12.
184	loss of interaction with tcf12.
345	disrupts tetramerization, disrupts aml1-mtg8/eto interaction with tcf12, decreases aml1-mtg8/eto interaction with runx1t
352–353	decreases interaction with tcf12, no effect on oligomerization. impairs aml1-mtg8/eto activity in hematopoietic stem/pro
357	disrupts tetramerization, disrupts aml1-mtg8/eto interaction with tcf12, decreases aml1-mtg8/eto interaction with runx1t
360	disrupts tetramerization, disrupts aml1-mtg8/eto interaction with tcf12, decreases aml1-mtg8/eto interaction with runx1t
361	disrupts tetramerization, disrupts aml1-mtg8/eto interaction with tcf12, decreases aml1-mtg8/eto interaction with runx1t
375	disrupts tetramerization, disrupts aml1-mtg8/eto interaction with tcf12, decreases aml1-mtg8/eto interaction with runx1t
378	disrupts tetramerization, disrupts aml1-mtg8/eto interaction with tcf12, decreases aml1-mtg8/eto interaction with runx1t
379–381	disrupts interaction with tcf12, no effect on oligomerization. impairs aml1-mtg8/eto activity in hematopoietic stem/prog
389	disrupts tetramerization, disrupts aml1-mtg8/eto interaction with tcf12, decreases aml1-mtg8/eto interaction with runx1t
547	causes unfolding of the mynd-type zinc finger domain.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 364 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, TAATAAT_MIR126, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GCANCTGNY_MYOD_Q6, AREB6_01, TGACCTY_ERR1_Q2, TAL1ALPHAE47_01, USF_C, LIEN_BREAST_CARCINOMA_METAPLASTIC, CAGCTG_AP4_Q5, EFC_Q6

GO Biological Process (4): DNA-templated transcription (GO:0006351), negative regulation of fat cell differentiation (GO:0045599), negative regulation of DNA-templated transcription (GO:0045892), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): DNA binding (GO:0003677), transcription corepressor activity (GO:0003714), zinc ion binding (GO:0008270), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear matrix (GO:0016363)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	2
nuclear lumen	2
cellular anatomical structure	2
gene expression	1
RNA biosynthetic process	1
fat cell differentiation	1
negative regulation of cell differentiation	1
regulation of fat cell differentiation	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
nucleic acid binding	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
transition metal ion binding	1
transcription factor binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2234 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RUNX1T1	RUNX1	Q01196	998
RUNX1T1	NCOR2	Q9Y618	824
RUNX1T1	RARA	P10276	813
RUNX1T1	MYH11	P35749	799
RUNX1T1	ZMYND10	O75800	785
RUNX1T1	NCOR1	O75376	782
RUNX1T1	CBFB	Q13951	780
RUNX1T1	TCF12	Q99081	747
RUNX1T1	MECOM	Q03112	735
RUNX1T1	ZBTB16	Q05516	702
RUNX1T1	FLT3	P36888	695
RUNX1T1	NPM1	P06748	692
RUNX1T1	GFI1B	Q5VTD9	662
RUNX1T1	CBFA2T2	O43439	649
RUNX1T1	KMT2A	Q03164	625

IntAct

62 interactions, top by confidence:

A	B	Type	Score
PRDM14	CBFA2T2	psi-mi:“MI:0914”(association)	0.860
PSMC5	PSMD11	psi-mi:“MI:0914”(association)	0.730
RUNX1T1	NCOR1	psi-mi:“MI:0407”(direct interaction)	0.720
RUNX1T1	NCOR1	psi-mi:“MI:0915”(physical association)	0.720
RUNX1T1	NCOR1	psi-mi:“MI:0914”(association)	0.720
RUNX1T1	Son	psi-mi:“MI:0915”(physical association)	0.620
Son	RUNX1T1	psi-mi:“MI:0915”(physical association)	0.620
RUNX1T1	PRDM14	psi-mi:“MI:0915”(physical association)	0.550
CBFA2T3	CBFA2T2	psi-mi:“MI:0914”(association)	0.530
TCF4	CBFA2T3	psi-mi:“MI:0914”(association)	0.530
SYCE3	RER1	psi-mi:“MI:0914”(association)	0.530
SP1	RUNX1T1	psi-mi:“MI:0915”(physical association)	0.520
RUNX1T1	SP1	psi-mi:“MI:0915”(physical association)	0.520
SPOP	RUNX1T1	psi-mi:“MI:2364”(proximity)	0.470
RUNX1T1	SPOP	psi-mi:“MI:2364”(proximity)	0.470
SPOP	RUNX1T1	psi-mi:“MI:0915”(physical association)	0.470
RUNX1T1	RUNX1T1	psi-mi:“MI:0407”(direct interaction)	0.440
ZNF652	RUNX1T1	psi-mi:“MI:0915”(physical association)	0.400
SON	RUNX1T1	psi-mi:“MI:0915”(physical association)	0.400
RUNX1T1	EFHC2	psi-mi:“MI:0915”(physical association)	0.370
RUNX1T1	TCF12	psi-mi:“MI:0915”(physical association)	0.370
RUNX1T1	GSE1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (196): EPS8 (Two-hybrid), MEOX2 (Two-hybrid), STX11 (Two-hybrid), ZMYM4 (Two-hybrid), LPXN (Two-hybrid), HOMER3 (Two-hybrid), SPRY2 (Two-hybrid), MID2 (Two-hybrid), GSE1 (Two-hybrid), ABI3 (Two-hybrid), NECAB2 (Two-hybrid), PRDM14 (Two-hybrid), C19orf57 (Two-hybrid), CPSF7 (Two-hybrid), EFHC2 (Two-hybrid)

ESM2 similar proteins: A2RSY1, F1R7R1, O54972, O75069, O75151, O88873, P0CH95, P49140, P58929, Q02225, Q06455, Q13233, Q1LY51, Q24767, Q2VPU4, Q2YDD2, Q3KR73, Q499B3, Q4VGL6, Q5F3B1, Q5PQS6, Q5TC82, Q60416, Q60698, Q61909, Q62415, Q62739, Q66IV1, Q6F6B3, Q6NUC6, Q6NYU6, Q7Z3K3, Q80TJ7, Q80W04, Q8BZH4, Q8CHY6, Q8CID0, Q8K2L8, Q8NEM7, Q8TEK3

Diamond homologs: O00268, O43439, O54972, O70374, O75081, O75398, O77562, O88450, P47825, Q06455, Q5F3B1, Q61909, Q9IAB2, Q9Z1T5, O88873, P23497, P58929, Q13342, Q3KRF1, Q8BVK9, Q921C6, Q9H930, Q9HB58, Q9UKD1, Q24180

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GATA1	“up-regulates quantity by expression”	RUNX1T1	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 6 cancer types — HCC, LGGNOS, LUSC, MEL, PRAD, SCLC.

Clinical variants and AI predictions

ClinVar

107 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	78
Likely benign	9
Benign	7

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
599590	NM_175634.3(RUNX1T1):c.177_178insT (p.Pro60fs)	Pathogenic
638625	NM_175635.3(RUNX1T1):c.127A>C (p.Thr43Pro)	Likely pathogenic

SpliceAI

3387 predictions. Top by Δscore:

Variant	Effect	Δscore
8:91960516:CT:C	acceptor_gain	1.0000
8:91970652:CCTCA:C	donor_loss	1.0000
8:91970653:CTCAC:C	donor_loss	1.0000
8:91970654:TCA:T	donor_loss	1.0000
8:91970655:CAC:C	donor_loss	1.0000
8:91970657:C:G	donor_loss	1.0000
8:91970657:CCTCG:C	donor_gain	1.0000
8:91970671:T:TA	donor_gain	1.0000
8:91970857:C:T	acceptor_gain	1.0000
8:91970861:C:CT	acceptor_gain	1.0000
8:91970862:A:T	acceptor_gain	1.0000
8:91970866:C:CT	acceptor_gain	1.0000
8:91970866:C:T	acceptor_gain	1.0000
8:91970867:A:T	acceptor_gain	1.0000
8:91970871:C:CT	acceptor_gain	1.0000
8:91970871:C:T	acceptor_gain	1.0000
8:91970872:A:T	acceptor_gain	1.0000
8:91975903:A:AC	donor_gain	1.0000
8:91975904:C:CC	donor_gain	1.0000
8:91975904:CCAG:C	donor_gain	1.0000
8:91975974:C:CC	acceptor_gain	1.0000
8:91986321:AACAG:A	acceptor_gain	1.0000
8:91986322:ACAG:A	acceptor_gain	1.0000
8:91986323:CAG:C	acceptor_gain	1.0000
8:91986323:CAGC:C	acceptor_gain	1.0000
8:91986324:AG:A	acceptor_gain	1.0000
8:91986325:GCT:G	acceptor_loss	1.0000
8:91986326:C:CC	acceptor_gain	1.0000
8:91986327:T:A	acceptor_loss	1.0000
8:91986330:T:TC	acceptor_gain	1.0000

AlphaMissense

3961 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:91960404:A:C	C551W	1.000
8:91960405:C:A	C551F	1.000
8:91960405:C:G	C551S	1.000
8:91960405:C:T	C551Y	1.000
8:91960406:A:G	C551R	1.000
8:91960406:A:T	C551S	1.000
8:91960414:T:G	H548P	1.000
8:91960415:G:C	H548D	1.000
8:91960416:G:C	H547Q	1.000
8:91960416:G:T	H547Q	1.000
8:91960417:T:C	H547R	1.000
8:91960418:G:C	H547D	1.000
8:91960418:G:T	H547N	1.000
8:91960425:C:A	W544C	1.000
8:91960425:C:G	W544C	1.000
8:91960426:C:A	W544L	1.000
8:91960426:C:G	W544S	1.000
8:91960427:A:C	W544G	1.000
8:91960427:A:G	W544R	1.000
8:91960427:A:T	W544R	1.000
8:91960429:T:A	D543V	1.000
8:91960429:T:C	D543G	1.000
8:91960429:T:G	D543A	1.000
8:91960430:C:G	D543H	1.000
8:91960434:G:C	H541Q	1.000
8:91960434:G:T	H541Q	1.000
8:91960435:T:G	H541P	1.000
8:91960436:G:C	H541D	1.000
8:91960436:G:T	H541N	1.000
8:91960437:C:A	Q540H	1.000

dbSNP variants (sampled 300 via entrez): RS1000059307 (8:92025938 T>C), RS1000061993 (8:92059186 T>G), RS1000108727 (8:92065802 G>C), RS1000145213 (8:91971183 G>T), RS1000145912 (8:92086333 C>T), RS1000154925 (8:92069277 T>C), RS1000162670 (8:92062775 T>C), RS1000172065 (8:91998077 A>C), RS1000207248 (8:91991404 A>G), RS1000234472 (8:92035043 C>T), RS1000251661 (8:91979107 C>A,G), RS1000276511 (8:92063062 T>G), RS1000286679 (8:91959411 C>T), RS1000293210 (8:92102809 C>G,T), RS1000298814 (8:92093188 A>T)

Disease associations

OMIM: gene MIM:133435 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (2): NK-cell enteropathy (MONDO:0016996), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): NK-cell enteropathy (Orphanet:263665)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST003030_2	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	6.000000e-06
GCST005316_89	Intelligence (MTAG)	3.000000e-08
GCST006979_468	Heel bone mineral density	1.000000e-09
GCST007323_70	Risk-taking tendency (4-domain principal component model)	2.000000e-11
GCST007323_74	Risk-taking tendency (4-domain principal component model)	5.000000e-11
GCST007325_281	General risk tolerance (MTAG)	9.000000e-13
GCST007325_34	General risk tolerance (MTAG)	4.000000e-08
GCST007325_77	General risk tolerance (MTAG)	7.000000e-10
GCST007325_88	General risk tolerance (MTAG)	1.000000e-09
GCST007326_62	Number of sexual partners	5.000000e-09
GCST007327_166	Smoking status (ever vs never smokers)	1.000000e-10
GCST007327_221	Smoking status (ever vs never smokers)	3.000000e-13
GCST007576_259	Chronotype	9.000000e-12
GCST007603_4	Smoking initiation	2.000000e-09
GCST008369_2	Plasma anti-thyroglobulin levels	3.000000e-06
GCST008810_17	Smoking initiation (ever regular vs never regular)	2.000000e-09
GCST010988_305	Adult body size	2.000000e-08
GCST011703_89	Smoking initiation	3.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007679	oppositional defiant disorder measurement
EFO:0004337	intelligence
EFO:0009270	heel bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0008328	chronotype measurement
EFO:0005670	smoking initiation

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	7
trichostatin A	affects cotreatment, increases expression	3
methylmercuric chloride	increases expression	2
bisphenol A	decreases methylation, increases expression	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Vorinostat	increases expression, decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases methylation, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
HDN-1 compound	decreases expression	1
2-butenal	decreases expression	1
zinc chromate	increases abundance, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
mercuric bromide	increases expression	1
chromium hexavalent ion	increases expression, increases abundance	1
CGP 52608	increases reaction, affects binding	1
tanespimycin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Cadmium	decreases expression, increases abundance	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Lead	affects splicing	1
Lipopolysaccharides	increases expression, affects response to substance	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0589	Kasumi-1	Cancer cell line	Male
CVCL_2196	SKNO-1	Cancer cell line	Male
CVCL_JY44	Kasumi-1 R48	Cancer cell line	Male
CVCL_JY45	Kasumi-1 PR48	Cancer cell line	Male

Clinical trials (associated diseases)

202 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice