Myelodysplastic syndrome

Summary

Myelodysplastic syndrome (MONDO:0018881) is a disease (an umbrella term covering 8 Mondo subtypes) caused by variants in ERG and GATA2, with 27 cohort genes (10 GWAS associations across 6 studies) and 2,094 clinical trials. The dominant Reactome pathway is mRNA Splicing - Major Pathway (5 cohort genes). Molecularly, TP53 Mutation confers sensitivity to Azacitidine + Eprenetapopt in Myelodysplastic Syndrome (CIViC Level B). Top therapeutic interventions include cyclophosphamide anhydrous, azacitidine, and decitabine.

At a glance

• Prevalence: 1-9 / 100 000 (Germany) [Orphanet-validated]
• Causal genes: ERG (GenCC Strong), GATA2 (GenCC Strong)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 27
• GWAS associations: 10
• ClinVar variants: 76
• Clinical trials: 2,094
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Epidemiology

Prevalence records

17 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1.5	Europe	Validated
Lifetime Prevalence	1-9 / 100 000	5.02	Europe	Validated
Annual incidence	1-9 / 100 000	4.15	Germany	Validated
Annual incidence	1-9 / 100 000	6.4	France	Validated
Annual incidence	1-9 / 100 000	3.35	United States	Validated
Annual incidence	1-9 / 1 000 000	0.5	Romania	Validated
Annual incidence	1-9 / 100 000	8.1	Spain	Validated
Annual incidence	1-9 / 100 000	1.95	Poland	Validated
Annual incidence	1-9 / 100 000	3.8	Switzerland	Validated
Point prevalence	1-9 / 100 000	7	Germany	Validated
Point prevalence	1-9 / 100 000	6.2	Poland	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated
Annual incidence	1-9 / 100 000	5.4	Greece	Not yet validated
Annual incidence	1-9 / 100 000	8.5	United Kingdom	Not yet validated
Annual incidence	1-9 / 100 000	3.5	Sweden	Not yet validated
Point prevalence	1-9 / 100 000	1.35	Japan	Not yet validated
Point prevalence	1-5 / 10 000	15	United States	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	myelodysplastic syndrome
Mondo ID	MONDO:0018881
EFO	EFO:0000198
OMIM	614286
Orphanet	52688
DOID	DOID:0050908
ICD-10-CM	D46
NCIT	C3247
SNOMED CT	109995007
UMLS	C3463824
MedGen	483005
GARD	0007132
MedDRA	10028532
NORD	1480
Is cancer (heuristic)	no

Also known as: dysmyelopoietic syndrome · hematopoeitic - myelodysplastic syndrome (MDS) · MDS · MDS, unclassifiable · MDS-U · myelodysplasia · myelodysplastic neoplasm · myelodysplastic syndrome · myelodysplastic syndrome, somatic · myelodysplastic syndrome, unclassifiable · myelodysplastic syndrome/neoplasm · Myelodysplastic Syndromes · myelodysplastic syndromes · oligoblastic leukaemia · oligoblastic leukemia · preleukemia · smoldering leukemia · smouldering leukaemia

Data availability: 76 ClinVar variants · 10 GWAS associations (6 studies) · 2 GenCC gene-disease records · 37 cell lines · 3 intOGen driver records.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › myeloid hemopathy › myelodysplastic syndrome

Related subtypes (3): myeloid/lymphoid neoplasms associated with eosinophilia and abnormality of PDGFRA, PDGFRB, FGFR1 or JAK2, myeloproliferative neoplasm, myelodysplastic/myeloproliferative disease

Subtypes (8): myelodysplastic syndrome with single lineage dysplasia, myelodysplastic syndrome associated with isolated del(5q), refractory anemia with excess blasts in transformation, myelodysplastic syndrome with ring sideroblasts, myelodysplastic syndrome with multilineage dysplasia, myelodysplastic syndrome with excess blasts, familial monosomy 7 syndrome, childhood myelodysplastic syndrome

Genetics & variants

GWAS landscape

10 GWAS associations across 6 studies. Top hits map to 8 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12203592	3e-12	IRF4	T	1.38
rs78898975	1e-08	TAF2	C	5.87
rs1206818	7e-08	EYA2	A	1.41
rs2947170	1e-07	LINC02375 - Y_RNA	T	1.65
rs1634783	8e-07	LINC02571 - HLA-B	G	1.32
rs341274	4e-06	EFNA5	A	1.35
rs34539210	4e-06	TAFA4	T	1.39
rs4404050	6e-06	CRAT37	T	1.31
rs6683416	6e-06	PLA2G4A	C	1.37
rs7099032	9e-06	GRID1	A	1.35

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90020096	Wang J	2021	1,769	2,814	Genome-Wide Association Analyses Identify Variants in IRF4 Associated With Acute Myeloid Leukemia and Myelodysplastic Syndrome Susceptibility.
GCST009516	McGraw KL	2019	907	5,605	Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis.
GCST90042662	Jiang L	2021	521	455,827	A generalized linear mixed model association tool for biobank-scale data.
GCST90020098	Wang J	2021	444	2,814	Genome-Wide Association Analyses Identify Variants in IRF4 Associated With Acute Myeloid Leukemia and Myelodysplastic Syndrome Susceptibility.
GCST90043940	Jiang L	2021	105	456,243	A generalized linear mixed model association tool for biobank-scale data.
GCST90020097	Wang J	2021	96	2,814	Genome-Wide Association Analyses Identify Variants in IRF4 Associated With Acute Myeloid Leukemia and Myelodysplastic Syndrome Susceptibility.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	10

MAF distribution

Bucket	Variants
common (>=0.05)	9
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	10

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12203592	6	396321	C>G,T	0.14	intron_variant	IRF4	3e-12	Tier 4: intronic/intergenic
rs78898975	8	119803144	T>C	0.015	intron_variant	TAF2	1e-08	Tier 4: intronic/intergenic
rs1206818	20	47077153	A>C,G,T	0.23	intron_variant	EYA2	7e-08	Tier 4: intronic/intergenic
rs2947170	12	127545976	A>C,T	0.07	intron_variant	LINC02375 - Y_RNA	1e-07	Tier 4: intronic/intergenic
rs1634783	6	31315827	G>A,C	0.5	intron_variant	LINC02571 - HLA-B	8e-07	Tier 4: intronic/intergenic
rs341274	5	107549741	A>C,G,T	0.22	intron_variant	EFNA5	4e-06	Tier 4: intronic/intergenic
rs34539210	3	68910754	T>C,G	0.24	intron_variant	TAFA4	4e-06	Tier 4: intronic/intergenic
rs4404050	15	91593747	T>A,C	0.33	intron_variant	CRAT37	6e-06	Tier 4: intronic/intergenic
rs6683416	1	186944695	A>C,G,T	0.25	intron_variant	PLA2G4A	6e-06	Tier 4: intronic/intergenic
rs7099032	10	85873038	A>C	0.25	intron_variant	GRID1	9e-06	Tier 4: intronic/intergenic

ClinVar germline variants

76 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 14 conflicting classifications of pathogenicity, 13 likely pathogenic, 8 benign/likely benign, 6 pathogenic, 6 pathogenic/likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30986	NM_015338.6(ASXL1):c.1210C>T (p.Arg404Ter)	ASXL1	Pathogenic	criteria provided, multiple submitters, no conflicts
521420	NM_015338.6(ASXL1):c.4127dup (p.Pro1377fs)	ASXL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620281	NM_015338.6(ASXL1):c.2077C>T (p.Arg693Ter)	ASXL1	Pathogenic	criteria provided, multiple submitters, no conflicts
807543	NM_015338.6(ASXL1):c.2036dup (p.Gly680fs)	ASXL1	Pathogenic	criteria provided, single submitter
29711	NM_032638.5(GATA2):c.1061C>T (p.Thr354Met)	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
29722	NM_032638.5(GATA2):c.1065_1067del (p.Thr358del)	GATA2	Pathogenic	criteria provided, single submitter
4262144	NM_032638.5(GATA2):c.46del (p.Val16fs)	GATA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
472431	NM_032638.5(GATA2):c.1081C>T (p.Arg361Cys)	GATA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800686	NM_032638.5(GATA2):c.405_409delinsGTA (p.Gly136fs)	GATA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208722	NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219098	NM_012433.4(SF3B1):c.1998G>T (p.Lys666Asn)	SF3B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686257	NM_001127208.3(TET2):c.2029_2032del (p.Cys677fs)	TET2	Pathogenic	criteria provided, single submitter
1705316	NM_015338.6(ASXL1):c.2068_2069del (p.Asp690fs)	ASXL1	Likely pathogenic	criteria provided, single submitter
3024329	NM_015338.6(ASXL1):c.3747_3748del (p.Met1249fs)	ASXL1	Likely pathogenic	criteria provided, single submitter
2500300	NM_032638.5(GATA2):c.1080G>A (p.Trp360Ter)	GATA2	Likely pathogenic	criteria provided, single submitter
2690920	NM_032638.5(GATA2):c.1341C>G (p.Ser447Arg)	GATA2	Likely pathogenic	criteria provided, single submitter
3588362	NM_032638.5(GATA2):c.345del (p.Trp116fs)	GATA2	Likely pathogenic	criteria provided, single submitter
846616	NM_032638.5(GATA2):c.1114G>A (p.Ala372Thr)	GATA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
975812	NC_000003.11:g.(128203154_128202733)_(128202028_128201205)del	GATA2	Likely pathogenic	criteria provided, single submitter
9600	NC_012920.1(MT-TL1):m.3242G>A	MT-TL1	Likely pathogenic	reviewed by expert panel
376005	NM_012433.4(SF3B1):c.1998G>C (p.Lys666Asn)	SF3B1	Likely pathogenic	criteria provided, single submitter
4278404	NM_012433.4(SF3B1):c.1866G>C (p.Glu622Asp)	SF3B1	Likely pathogenic	criteria provided, single submitter
1686651	NM_001127208.3(TET2):c.3804-2A>C	TET2	Likely pathogenic	no assertion criteria provided
2681590	NM_001127208.3(TET2):c.3955-2A>G	TET2	Likely pathogenic	criteria provided, single submitter
3589730	NM_001127208.3(TET2):c.797del (p.His266fs)	TET2	Likely pathogenic	criteria provided, single submitter
1698850	NM_016222.4(DDX41):c.1621+5G>T	DDX41	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184011	NM_032638.5(GATA2):c.1168A>G (p.Lys390Glu)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
404078	NM_032638.5(GATA2):c.1286G>C (p.Ser429Thr)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
404080	NM_032638.5(GATA2):c.445G>A (p.Gly149Arg)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
404088	NM_032638.5(GATA2):c.1348G>A (p.Gly450Arg)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 99 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ERG	Strong	Autosomal dominant	myelodysplastic syndrome	2
GATA2	Strong	Autosomal dominant	myelodysplastic syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SF3B1	Orphanet:39044	Uveal melanoma
SF3B1	Orphanet:75564	Acquired idiopathic sideroblastic anemia
ASXL1	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
ASXL1	Orphanet:97297	Bohring-Opitz syndrome
ASXL1	Orphanet:98823	Chronic myelomonocytic leukemia
ASXL1	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
ASXL1	Orphanet:98850	Aggressive systemic mastocytosis
TET2	Orphanet:100019	Myelodysplastic neoplasm with increased blasts type 1
TET2	Orphanet:100020	Myelodysplastic neoplasm with increased blasts type 2
TET2	Orphanet:3318	Essential thrombocythemia
TET2	Orphanet:664729	EBV-induced lymphoproliferative disease due to TET2 deficiency
TET2	Orphanet:75564	Acquired idiopathic sideroblastic anemia
TET2	Orphanet:824	Primary myelofibrosis
TET2	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
TET2	Orphanet:98826	Myelodysplastic neoplasm with low blasts
TET2	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
TET2	Orphanet:98850	Aggressive systemic mastocytosis
GATA2	Orphanet:228423	GATA2 deficiency spectrum
RUNX1	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
RUNX1	Orphanet:521	Chronic myeloid leukemia
RUNX1	Orphanet:71290	Familial platelet disorder with associated myeloid malignancy
RUNX1	Orphanet:98850	Aggressive systemic mastocytosis
SRSF2	Orphanet:98823	Chronic myelomonocytic leukemia
SRSF2	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
SRSF2	Orphanet:98850	Aggressive systemic mastocytosis
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
BCOR	Orphanet:2712	Oculofaciocardiodental syndrome
BCOR	Orphanet:457246	Clear cell sarcoma of kidney
BCOR	Orphanet:520	Acute promyelocytic leukemia
BCOR	Orphanet:568	Microphthalmia, Lenz type
DNMT3A	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma

Cohort genes → proteins

27 cohort genes, 25 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	5
civic_only	10
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SF3B1	HGNC:10768	ENSG00000115524	O75533	Splicing factor 3B subunit 1	clinvar,civic_evidence
ASXL1	HGNC:18318	ENSG00000171456	Q8IXJ9	Polycomb group protein ASXL1	clinvar,civic_evidence
TET2	HGNC:25941	ENSG00000168769	Q6N021	Methylcytosine dioxygenase TET2	clinvar,civic_evidence
GATA2	HGNC:4171	ENSG00000179348	P23769	Endothelial transcription factor GATA-2	gencc,clinvar
RUNX1	HGNC:10471	ENSG00000159216	Q01196	Runt-related transcription factor 1	civic_evidence
SRSF2	HGNC:10783	ENSG00000161547	Q01130	Serine/arginine-rich splicing factor 2	civic_evidence
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	civic_evidence
U2AF1	HGNC:12453	ENSG00000160201	Q01081	Splicing factor U2AF 35 kDa subunit	civic_evidence
BCOR	HGNC:20893	ENSG00000183337	Q6W2J9	BCL-6 corepressor	civic_evidence
DNMT3A	HGNC:2978	ENSG00000119772	Q9Y6K1	DNA (cytosine-5)-methyltransferase 3A	civic_evidence
ERG	HGNC:3446	ENSG00000157554	P11308	Transcriptional regulator ERG	gencc
EZH2	HGNC:3527	ENSG00000106462	Q15910	Histone-lysine N-methyltransferase EZH2	civic_evidence
FLT3	HGNC:3765	ENSG00000122025	P36888	Receptor-type tyrosine-protein kinase FLT3	civic_evidence
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	civic_evidence
IDH2	HGNC:5383	ENSG00000182054	P48735	Isocitrate dehydrogenase [NADP], mitochondrial	civic_evidence
SF3B2	HGNC:10769	ENSG00000087365	Q13435	Splicing factor 3B subunit 2	clinvar
SAMD9	HGNC:1348	ENSG00000205413	Q5K651	Sterile alpha motif domain-containing protein 9	clinvar
DDX41	HGNC:18674	ENSG00000183258	Q9UJV9	Probable ATP-dependent RNA helicase DDX41	clinvar
TAFA4	HGNC:21591	ENSG00000163377	Q96LR4	Chemokine-like protein TAFA-4	gwas
EFNA5	HGNC:3225	ENSG00000184349	P52803	Ephrin-A5	gwas
ERBB2	HGNC:3430	ENSG00000141736	P04626	Receptor tyrosine-protein kinase erbB-2	clinvar
EYA2	HGNC:3520	ENSG00000064655	O00167	Protein phosphatase EYA2	gwas
TET2-AS1	HGNC:41125	ENSG00000251586		TET2 antisense RNA 1	clinvar
GNB1	HGNC:4396	ENSG00000078369	P62873	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	clinvar
GRID1	HGNC:4575	ENSG00000182771	Q9ULK0	Glutamate receptor ionotropic, delta-1	gwas
MT-TL1	HGNC:7490	ENSG00000209082		mitochondrially encoded tRNA-Leu (UUA/G) 1	clinvar
PLA2G4A	HGNC:9035	ENSG00000116711	P47712	Cytosolic phospholipase A2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SF3B1	Splicing factor 3B subunit 1	Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs.
ASXL1	Polycomb group protein ASXL1	Probable Polycomb group (PcG) protein involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG).
TET2	Methylcytosine dioxygenase TET2	Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation.
GATA2	Endothelial transcription factor GATA-2	Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells.
RUNX1	Runt-related transcription factor 1	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
SRSF2	Serine/arginine-rich splicing factor 2	Necessary for the splicing of pre-mRNA.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
U2AF1	Splicing factor U2AF 35 kDa subunit	Plays a critical role in both constitutive and enhancer-dependent splicing by mediating protein-protein interactions and protein-RNA interactions required for accurate 3’-splice site selection.
BCOR	BCL-6 corepressor	Transcriptional corepressor.
DNMT3A	DNA (cytosine-5)-methyltransferase 3A	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.
ERG	Transcriptional regulator ERG	Transcriptional regulator.
EZH2	Histone-lysine N-methyltransferase EZH2	Catalytic subunit of the PRC2/EED-EZH2 complex, a Polycomb group (PcG) complex that methylates ‘Lys-9’ (H3K9me) and ‘Lys-27’ (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene.
FLT3	Receptor-type tyrosine-protein kinase FLT3	Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells.
IDH1	Isocitrate dehydrogenase [NADP] cytoplasmic	Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase.
IDH2	Isocitrate dehydrogenase [NADP], mitochondrial	Plays a role in intermediary metabolism and energy production.
SF3B2	Splicing factor 3B subunit 2	Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs.
SAMD9	Sterile alpha motif domain-containing protein 9	Double-stranded nucleic acid binding that acts as an antiviral factor by playing an essential role in the formation of cytoplasmic antiviral granules.
DDX41	Probable ATP-dependent RNA helicase DDX41	Multifunctional protein that participates in many aspects of cellular RNA metabolism.
TAFA4	Chemokine-like protein TAFA-4	Modulates injury-induced and chemical pain hypersensitivity.
EFNA5	Ephrin-A5	Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development.
ERBB2	Receptor tyrosine-protein kinase erbB-2	Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding.
EYA2	Protein phosphatase EYA2	Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5.
GNB1	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.
GRID1	Glutamate receptor ionotropic, delta-1	Member of the ionotropic glutamate receptor family, which plays a crucial role in synaptic organization and signal transduction in the central nervous system.
PLA2G4A	Cytosolic phospholipase A2	Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response.

Protein-family classification

Druggable: 8 · Difficult: 6 · Unknown: 13 · Druggable fraction: 0.3

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Complement	1	9.9×	0.288
Enzyme (other)	5	2.2×	0.288
Kinase	2	2.0×	0.509
Scaffold/PPI	2	1.3×	0.562
Transcription factor	4	1.2×	0.562
Other/Unknown	13	0.9×	0.841

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SF3B1	Other/Unknown	no		ARM-like, SF3b_su1, ARM-type_fold
ASXL1	Other/Unknown	no		Asxl_HARE-HTH, ASX/ASX-like, ASX-like_PHD
TET2	Other/Unknown	no		2OGFeDO_JBP1/TET_oxygenase_dom, TET1/2/3, TET_oxygenase
GATA2	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, TF_GATA-2/3
RUNX1	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
SRSF2	Other/Unknown	no		RRM_dom, RRM_euk-type, Nucleotide-bd_a/b_plait_sf
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
U2AF1	Transcription factor	no		RRM_dom, Znf_CCCH, RRM_euk-type
BCOR	Scaffold/PPI	no		Ankyrin_rpt, BCOR, PUFD
DNMT3A	Complement	yes	2.1.1.37	PWWP_dom, C5_MeTfrase, C5_DNA_meth_AS
ERG	Other/Unknown	no		Ets_dom, Pointed_dom, SAM/pointed_sf
EZH2	Enzyme (other)	yes	2.1.1.356	SANT/Myb, SET_dom, EZH1/EZH2_N
FLT3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
IDH2	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
SF3B2	Other/Unknown	no		SAP_dom, PSP_pro-rich, DUF382
SAMD9	Other/Unknown	no		SAM, SAM/pointed_sf, P-loop_NTPase
DDX41	Other/Unknown	no		Helicase_C-like, DEAD/DEAH_box_helicase_dom, Helicase_ATP-bd
TAFA4	Other/Unknown	no		Chemokine-like_TAFA, TAFA_chemokine-like
EFNA5	Other/Unknown	no		Ephrin_RBD, Cupredoxin, Ephrin_CS
ERBB2	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
EYA2	Enzyme (other)	yes	3.1.3.48	EYA_dom, EYA, HAD-like_sf
TET2-AS1	Other/Unknown	no
GNB1	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
GRID1	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
MT-TL1	Other/Unknown	no
PLA2G4A	Enzyme (other)	yes	3.1.1.4	C2_dom, LysoPLipase_cat_dom, Acyl_Trfase/lysoPLipase

Expression context

Cohort genes with no expression data: 0.

26 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	5
ganglionic eminence	5
adrenal tissue	3
sural nerve	3
tendon of biceps brachii	3
epithelium of nasopharynx	2
tibia	2
amniotic fluid	2
left uterine tube	2
seminal vesicle	2
olfactory segment of nasal mucosa	2
embryo	2
bone marrow	2
cortical plate	2
male germ line stem cell (sensu Vertebrata) in testis	2
lower esophagus mucosa	2
right frontal lobe	2
secondary oocyte	2
right uterine tube	2
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SF3B1	295	ubiquitous	marker	tibia, ventricular zone, epithelium of nasopharynx
ASXL1	294	ubiquitous	marker	sural nerve, sperm, adrenal tissue
TET2	249	ubiquitous	marker	palpebral conjunctiva, amniotic fluid, epithelium of nasopharynx
GATA2	273	ubiquitous	marker	seminal vesicle, right lung, left uterine tube
RUNX1	253	ubiquitous	marker	olfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus
SRSF2	295	ubiquitous	marker	tibia, embryo, tendon of biceps brachii
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
U2AF1	134	ubiquitous	marker	adenohypophysis, left uterine tube, bone marrow
BCOR	265	ubiquitous	marker	buccal mucosa cell, ganglionic eminence, cortical plate
DNMT3A	223	ubiquitous	marker	sural nerve, ganglionic eminence, ventricular zone
ERG	247	broad	marker	tendon of biceps brachii, descending thoracic aorta, thoracic aorta
EZH2	216	ubiquitous	marker	ganglionic eminence, ventricular zone, embryo
FLT3	166	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere, cerebellar cortex
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
IDH2	292	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle
SF3B2	292	ubiquitous	marker	ventricular zone, left testis, right testis
SAMD9	247	ubiquitous	marker	esophagus squamous epithelium, amniotic fluid, epithelium of esophagus
DDX41	274	ubiquitous	marker	granulocyte, right frontal lobe, lower esophagus mucosa
TAFA4	96	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, oocyte, secondary oocyte
EFNA5	258	ubiquitous	marker	hair follicle, Brodmann (1909) area 23, cervix squamous epithelium
ERBB2	276	ubiquitous	marker	lower esophagus mucosa, right uterine tube, sural nerve
EYA2	205	ubiquitous	marker	olfactory segment of nasal mucosa, calcaneal tendon, parotid gland
TET2-AS1	113	tissue_specific	marker	bone marrow cell, adrenal tissue, bone marrow
GNB1	295	ubiquitous	marker	cortical plate, ganglionic eminence, secondary oocyte
GRID1	180	broad	yes	prefrontal cortex, C1 segment of cervical spinal cord, spinal cord
MT-TL1	118	ubiquitous	marker	frontal cortex, right frontal lobe, caudate nucleus
PLA2G4A	248	ubiquitous	marker	seminal vesicle, cartilage tissue, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 36.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
ERBB2	9,659
EZH2	9,646
IDH1	5,464
RUNX1	4,994
GATA2	4,979
IDH2	4,912
DNMT3A	4,771
SF3B1	4,582
SF3B2	3,906

Intra-cohort edges

A	B	Sources
ASXL1	DNMT3A	string_interaction
ASXL1	EZH2	intact, string_interaction
ASXL1	FLT3	string_interaction
ASXL1	IDH1	string_interaction
ASXL1	IDH2	string_interaction
ASXL1	RUNX1	string_interaction
ASXL1	SRSF2	string_interaction
ASXL1	TET2	string_interaction
ASXL1	U2AF1	string_interaction
BCOR	EYA2	biogrid_interaction
DDX41	SAMD9	string_interaction
DDX41	SF3B1	intact
DNMT3A	EZH2	intact, string_interaction
DNMT3A	FLT3	string_interaction
DNMT3A	TET2	string_interaction
DNMT3A	U2AF1	string_interaction
ERG	SRSF2	string_interaction
EZH2	TET2	string_interaction
FLT3	IDH1	string_interaction
FLT3	IDH2	string_interaction
FLT3	RUNX1	string_interaction
FLT3	TET2	string_interaction
GATA2	RUNX1	string_interaction
GATA2	SAMD9	string_interaction
IDH1	IDH2	biogrid_interaction
IDH1	TET2	string_interaction
IDH1	TP53	string_interaction
IDH1	U2AF1	string_interaction
IDH2	TET2	string_interaction
RUNX1	SRSF2	string_interaction
SF3B1	SF3B2	string_interaction
SF3B1	SRSF2	string_interaction
SF3B1	U2AF1	string_interaction
SRSF2	TET2	string_interaction
SRSF2	U2AF1	intact, string_interaction
TET2	U2AF1	string_interaction

Structural data

PDB: 24 · AlphaFold-only: 1 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNB1	P62873	1,262
TP53	P04637	313
SF3B1	O75533	74
ERBB2	P04626	63
IDH1	O75874	61
SF3B2	Q13435	50
DNMT3A	Q9Y6K1	43
EZH2	Q15910	38
FLT3	P36888	11
IDH2	P48735	11
ERG	P11308	8
SAMD9	Q5K651	7
EYA2	O00167	7
TET2	Q6N021	6
EFNA5	P52803	6
RUNX1	Q01196	5
BCOR	Q6W2J9	5
DDX41	Q9UJV9	5
ASXL1	Q8IXJ9	4
SRSF2	Q01130	4
GRID1	Q9ULK0	3
PLA2G4A	P47712	3
GATA2	P23769	2
U2AF1	Q01081	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TAFA4	Q96LR4	85.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 239. Enrichment computed across 27 evidence-associated genes (20 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
mRNA Splicing - Major Pathway	5	13.7×	0.006	SF3B1, SF3B2, SRSF2, U2AF1, DDX41
mRNA Splicing - Minor Pathway	3	33.6×	0.007	SF3B1, SF3B2, SRSF2
mRNA Polyadenylation	4	17.6×	0.007	SF3B1, SF3B2, SRSF2, U2AF1
Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate	1	571.0×	0.017	IDH1
FLT3 mutants bind TKIs	1	571.0×	0.017	FLT3
KW2449-resistant FLT3 mutants	1	571.0×	0.017	FLT3
semaxanib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
crenolanib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
gilteritinib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
lestaurtinib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
midostaurin-resistant FLT3 mutants	1	571.0×	0.017	FLT3
pexidartinib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
ponatinib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
quizartinib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
sorafenib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
sunitinib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
tandutinib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
linifanib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
tamatinib-resistant FLT3 mutants	1	571.0×	0.017	FLT3
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	571.0×	0.017	TP53
ADP signalling through P2Y purinoceptor 1	2	45.7×	0.017	GNB1, PLA2G4A
mRNA Splicing	3	16.5×	0.017	SF3B1, SF3B2, SRSF2
Processing of Capped Intron-Containing Pre-mRNA	3	12.3×	0.017	SF3B1, SF3B2, SRSF2
Dengue Virus-Host Interactions	4	9.1×	0.017	SF3B1, SF3B2, SRSF2, U2AF1
phospho-PLA2 pathway	1	285.5×	0.031	PLA2G4A
NADPH regeneration	1	285.5×	0.031	IDH1
Regulation of TP53 Expression	1	285.5×	0.031	TP53
RUNX3 regulates RUNX1-mediated transcription	1	190.3×	0.038	RUNX1
NFE2L2 regulating TCA cycle genes	1	190.3×	0.038	IDH1
PLCG1 events in ERBB2 signaling	1	142.8×	0.038	ERBB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 25 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glyoxylate cycle	2	674.1×	9e-04	IDH1, IDH2
positive regulation of MAP kinase activity	3	77.8×	0.002	ERBB2, EZH2, FLT3
isocitrate metabolic process	2	269.6×	0.003	IDH1, IDH2
regulatory ncRNA-mediated heterochromatin formation	2	149.8×	0.006	DNMT3A, EZH2
negative regulation of glial cell proliferation	2	134.8×	0.006	TP53, IDH2
NADP+ metabolic process	2	122.6×	0.006	IDH1, IDH2
bone marrow development	2	122.6×	0.006	ASXL1, TP53
hemopoiesis	3	32.1×	0.006	ASXL1, RUNX1, FLT3
mRNA splicing, via spliceosome	4	14.7×	0.006	SF3B1, SF3B2, U2AF1, DDX41
RNA splicing	4	14.1×	0.006	SF3B1, SF3B2, SRSF2, U2AF1
positive regulation of transcription by RNA polymerase II	8	4.8×	0.006	SF3B1, ASXL1, TET2, GATA2, RUNX1, TP53, DDX41, ERG
negative regulation of neuroblast proliferation	2	96.3×	0.007	GATA2, TP53
2-oxoglutarate metabolic process	2	74.9×	0.010	IDH1, IDH2
myeloid cell differentiation	2	51.9×	0.019	TET2, RUNX1
positive regulation of transcription by RNA polymerase I	2	51.9×	0.019	SF3B1, ERBB2
U2-type prespliceosome assembly	2	49.9×	0.019	SF3B1, SF3B2
negative regulation of helicase activity	1	674.1×	0.022	TP53
regulation of phospholipid catabolic process	1	674.1×	0.022	IDH1
semicircular canal development	1	674.1×	0.022	GATA2
specification of axis polarity	1	674.1×	0.022	BCOR
cellular response to actinomycin D	1	674.1×	0.022	TP53
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	674.1×	0.022	TP53
negative regulation of G1 to G0 transition	1	674.1×	0.022	TP53
regulation of connective tissue replacement	1	674.1×	0.022	RUNX1
regulation of forebrain neuron differentiation	1	674.1×	0.022	GATA2
DNA methylation-dependent constitutive heterochromatin formation	2	43.5×	0.022	DNMT3A, EZH2
tricarboxylic acid cycle	2	40.9×	0.022	IDH1, IDH2
liver regeneration	2	40.9×	0.022	EZH2, FLT3
peptidyl-tyrosine phosphorylation	2	33.7×	0.023	ERBB2, FLT3
cell population proliferation	3	12.3×	0.025	DDX41, ERBB2, GNB1

Therapeutics

Drugs indicated for this disease

7 approved, 41 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Azacitidine	Approved (phase 4)
Cedazuridine	Approved (phase 4)
Decitabine	Approved (phase 4)
Deferasirox	Approved (phase 4)
Epoetin Alfa	Approved (phase 4)
Lenalidomide	Approved (phase 4)
Luspatercept	Approved (phase 4)
Aldesleukin	Phase 3 (in late-stage trials)
Alemtuzumab	Phase 3 (in late-stage trials)
Amphotericin B	Phase 3 (in late-stage trials)
Amsacrine	Phase 3 (in late-stage trials)
Arsenic Trioxide	Phase 3 (in late-stage trials)
Asparaginase	Phase 3 (in late-stage trials)
Busulfan	Phase 3 (in late-stage trials)
Cyclosporine	Phase 3 (in late-stage trials)
Cytarabine	Phase 3 (in late-stage trials)
Darbepoetin Alfa	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Epoetin Beta	Phase 3 (in late-stage trials)
Eprenetapopt	Phase 3 (in late-stage trials)
Etoposide	Phase 3 (in late-stage trials)
Filgrastim	Phase 3 (in late-stage trials)
Fludarabine	Phase 3 (in late-stage trials)
Fludarabine Phosphate	Phase 3 (in late-stage trials)
Gemtuzumab Ozogamicin	Phase 3 (in late-stage trials)
Hydrocortisone	Phase 3 (in late-stage trials)
Hydroxyurea	Phase 3 (in late-stage trials)
Idarubicin	Phase 3 (in late-stage trials)
Ivosidenib	Phase 3 (in late-stage trials)
Lemzoparlimab	Phase 3 (in late-stage trials)
Lonafarnib	Phase 3 (in late-stage trials)
Magrolimab	Phase 3 (in late-stage trials)
Melphalan	Phase 3 (in late-stage trials)
Methotrexate	Phase 3 (in late-stage trials)
Mycophenolate Mofetil	Phase 3 (in late-stage trials)
Nystatin	Phase 3 (in late-stage trials)
Rigosertib	Phase 3 (in late-stage trials)
Roxadustat	Phase 3 (in late-stage trials)
Sabatolimab	Phase 3 (in late-stage trials)
Sargramostim	Phase 3 (in late-stage trials)
Tamibarotene	Phase 3 (in late-stage trials)
Thalidomide	Phase 3 (in late-stage trials)
Thioguanine	Phase 3 (in late-stage trials)
Tipifarnib	Phase 3 (in late-stage trials)
Treosulfan	Phase 3 (in late-stage trials)
Tretinoin	Phase 3 (in late-stage trials)
Valspodar	Phase 3 (in late-stage trials)
Venetoclax	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetaminophen, Alisertib, Allopurinol, Amifostine, Anidulafungin, Ascorbic Acid, Asparaginase Erwinia Chrysanthemi, Axitinib, Belinostat, Bevacizumab, Bexarotene, Bezafibrate, Bortezomib, CPI 613, Calcitriol, Carboplatin, Cisplatin, Cladribine, Clofarabine, Daclizumab, Danazol, Daratumumab, Daunorubicin, Dexrazoxane, Diphenhydramine, Doxorubicin, Durvalumab, Eltrombopag, Enasidenib, Entinostat, Epacadostat, Erlotinib, Everolimus, Fedratinib, Gedatolisib, Gilteritinib, Guadecitabine, Hemin, Human Immunoglobulin G, Imetelstat, Incomplete Freund’S Adjuvant, Infliximab, Interferon Alfa, Lintuzumab, Maraviroc, Methylprednisolone, Metoclopramide, Midostaurin, Mitoxantrone, Motixafortide, Nivolumab, Nogapendekin Alfa, Olaparib, Oxiglutatione, PR1 LEUKEMIA PEPTIDE VACCINE, Palifermin, Panobinostat, Pegfilgrastim, Pegzilarginase, Pembrolizumab, Pevonedistat, Pracinostat, Prednisone, Rafutrombopag, Recombinant Human Thrombopoietin, Ridaforolimus, Rituximab, Romiplostim, Selinexor, Siltuximab, Sirolimus, Sodium Chloride, Sorafenib, Stanozolol, Tacrolimus Anhydrous, Temozolomide, Temsirolimus, Thiotepa, Valproic Acid, Volasertib, Voriconazole, Vorinostat, Vosaroxin.

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 10 · Phased (≥1): 16 · Undrugged: 11

Druggability breadth: 21 of 27 evidence-associated genes (78%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TET2	VADADUSTAT
RUNX1	APOMORPHINE HYDROCHLORIDE
TP53	NITROFURANTOIN
EZH2	TAZEMETOSTAT
FLT3	PONATINIB
IDH1	ENASIDENIB
IDH2	ENASIDENIB
ERBB2	CLOTRIMAZOLE
EYA2	BENZBROMARONE
PLA2G4A	ZAFIRLUKAST

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
FLT3	143	4
ERBB2	83	4
IDH1	10	4
IDH2	7	4
EZH2	6	4
TET2	3	4
PLA2G4A	3	4
RUNX1	2	4
EYA2	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VADADUSTAT	4	TET2
PANOBINOSTAT	4	TET2
DEFEROXAMINE	4	TET2
APOMORPHINE HYDROCHLORIDE	4	RUNX1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	ERBB2, TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FLT3	3,132	Binding:3096, Functional:24, ADMET:8, Toxicity:4
ERBB2	1,221	Binding:1136, Functional:79, ADMET:6
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
EZH2	839	Binding:833, Functional:6
IDH1	488	Binding:475, Functional:12, ADMET:1
DNMT3A	120	Binding:118, ADMET:1, Functional:1
PLA2G4A	95	Binding:91, Functional:4
IDH2	84	Binding:84
EYA2	36	Binding:33, Functional:3
TET2	24	Binding:24
SF3B1	22	Binding:22
RUNX1	20	Binding:17, Functional:3
SF3B2	20	Binding:20
ERG	14	Binding:10, Functional:3, ADMET:1
GNB1	12	Binding:12
SRSF2	8	Binding:8
U2AF1	8	Binding:8
DDX41	7	Binding:7
BCOR	2	Binding:2
GATA2	1	Binding:1
GRID1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase
EZH2	2.1.1.356	[histone H3]-lysine27 N-trimethyltransferase
FLT3	2.7.10.1	receptor protein-tyrosine kinase
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)
IDH2	1.1.1.42	isocitrate dehydrogenase (NADP+)
ERBB2	2.7.10.1	receptor protein-tyrosine kinase
EYA2	3.1.3.48	protein-tyrosine-phosphatase
PLA2G4A	3.1.1.4	phospholipase A2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TP53	869
DNMT3A	120
EZH2	839
FLT3	3,132
IDH1	488
ERBB2	1,221

Pharmacogenomics

Cohort genes with a PharmGKB record: 26; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
VADADUSTAT	4	TET2
PANOBINOSTAT	4	TET2
DEFEROXAMINE	4	TET2
APOMORPHINE HYDROCHLORIDE	4	RUNX1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	ERBB2, TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	TET2, RUNX1, TP53, EZH2, FLT3, IDH1, IDH2, ERBB2, EYA2, PLA2G4A
B	Phased (≥1) drug, not yet approved	6	SF3B1, SRSF2, U2AF1, SF3B2, DDX41, GNB1
C	Druggable family + PDB, no drug	1	DNMT3A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	10	ASXL1, GATA2, BCOR, ERG, SAMD9, TAFA4, EFNA5, TET2-AS1, GRID1, MT-TL1

Undrugged target profiles

11 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DNMT3A	120	EZH2
ASXL1	0	EZH2, TET2
GATA2	1	RUNX1
BCOR	2	—
ERG	14	—
SAMD9	0	—
TAFA4	0	—
EFNA5	0	—
TET2-AS1	0	—
GRID1	1	—
MT-TL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2,094.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	672
PHASE1/PHASE2	247
PHASE3	125
PHASE2/PHASE3	32
PHASE4	24

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00003398	PHASE4	COMPLETED	Bone Marrow Transplantation in Treating Patients With Hematologic Cancer
NCT00117507	PHASE4	COMPLETED	Study for the Treatment of Transfusional Iron Overload in Myelodysplastic Patients
NCT00202371	PHASE4	WITHDRAWN	Transfusion Effects in Myelodysplastic Patients: Limiting Exposure
NCT00361140	PHASE4	COMPLETED	Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
NCT00452660	PHASE4	COMPLETED	Evaluation the Effect of Exjade on Oxidative Stress in Low Risk Myelodysplastic Syndrome Patients With Iron Over Load
NCT00481143	PHASE4	COMPLETED	Efficacy and Safety of Deferasirox in Patients With Myelodysplastic Syndrome and Transfusion-dependent Iron Overload
NCT00487448	PHASE4	COMPLETED	SMD_FLAG-IDA_98: FLAG-IDA in Induction Treatment of High Risk Myelodysplastic Syndromes or Secondary Acute Myeloblastic Leukemia
NCT00488436	PHASE4	COMPLETED	Antithymocyte Globulin and Cyclosporine in Treating Low Risk Patients With Myelodysplastic Syndrome
NCT00564941	PHASE4	COMPLETED	Evaluating the Efficacy of Deferasirox in Transfusion Dependent Chronic Anaemias (Myelodysplastic Syndrome, Beta-thalassaemia Patients) With Chronic Iron Overload
NCT00673608	PHASE4	COMPLETED	Magnetic Resonance Imaging (MRI) Assessments of the Heart and Liver Iron Load in Patients With Transfusion Induced Iron Overload
NCT01011283	PHASE4	TERMINATED	To Demonstrate Superiority of Decitabine Over Azacitidine in Subjects With Intermediate- or High-risk MDS.
NCT01200355	PHASE4	COMPLETED	Posaconazole Versus Micafungin for Prophylaxis Against Invasive Fungal Infections During Neutropenia in Patients Undergoing Chemotherapy for Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia or Myelodysplastic Syndrome
NCT01201811	PHASE4	COMPLETED	Study of Azacitidine in Adult Taiwanese Subjects With Higher-Risk Myelodysplastic Syndromes (MDS)
NCT01250951	PHASE4	COMPLETED	This Study Will Evaluate Efficacy and Safety of Deferasirox in Patients With Myelodysplastic Syndromes (MDS), Thalassemia and Rare Anemia Types Having Transfusion-induced Iron Overload.
NCT01326845	PHASE4	TERMINATED	Myelodysplastic Syndrome (MDS) Gastrointestinal (GI) Tolerability Study
NCT01339988	PHASE4	UNKNOWN	Busulfan and Cyclophosphamide Instead of Total Boby Irradiation (TBI) and Cyclophosphamide for Hematological Malignancies Hematocrit (HCT)
NCT02013102	PHASE4	UNKNOWN	A Phase Ⅳ Study of Decitabine in Myelodysplastic Syndrome
NCT02145026	PHASE4	COMPLETED	A Study of Epoetin Beta Treatment in Anemic Participants With Myelodysplastic Syndrome (MDS)
NCT02875743	PHASE4	COMPLETED	King’s Invasive Aspergillosis Study II
NCT03176849	PHASE4	COMPLETED	A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 in Pediatric Patients Undergoing HSCT
NCT03335943	PHASE4	UNKNOWN	Myelodysplastic Syndrome–CDA-2 Hematological Improvement National Affirmation Study
NCT03598582	PHASE4	COMPLETED	Biological Predictive Factors of Response to ESA in Low Risk MDS Patients
NCT06004765	PHASE4	UNKNOWN	Efficacy and Safety of Lenalidomide Combined With Azacitidine vs Azacitidine in the Treatment of MDS-RS
NCT06006949	PHASE4	UNKNOWN	Roxadustat Combined With Luspatercept Versus Luspatercept Monotherapy in the Treatment of Refractory MDS-RS
NCT00843882	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia
NCT02521493	PHASE3	ACTIVE_NOT_RECRUITING	Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syndrome
NCT02598661	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Imetelstat (GRN163L) in Participants With International Prognostic Scoring System (IPSS) Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)
NCT03223961	PHASE3	ACTIVE_NOT_RECRUITING	A Trial Testing Early vs Late Onset of EPO Alfa Treatment in Lower Risk MDS
NCT03480360	PHASE3	ACTIVE_NOT_RECRUITING	Haploidentical Allogeneic Peripheral Blood Transplantation: Examining Checkpoint Immune Regulators’ Expression
NCT03682536	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Participants Who Require Red Blood Cell Transfusions and Are ESA Naïve
NCT04064060	PHASE3	RECRUITING	A Study to Evaluate Long-term Safety in Participants Who Have Participated in Other Luspatercept (ACE-536) Clinical Trials
NCT04173533	PHASE3	ACTIVE_NOT_RECRUITING	Randomised Study of Oral Azacitidine vs Placebo Maintenance in AML or MDS Patients After Allo-SCT
NCT04256317	PHASE2/PHASE3	RECRUITING	A Multi-phase Study of ASTX030 (Azacitidine and Cedazuridine) in Myeloid Neoplasm Alone or in Combination With Venetoclax in AML (AZTOUND Study)
NCT04401748	PHASE3	ACTIVE_NOT_RECRUITING	Study Of Venetoclax Tablet With Intravenous or Subcutaneous Azacitidine to Assess Change in Disease Activity In Adult Participants With Newly Diagnosed Higher-Risk Myelodysplastic Syndrome
NCT04547049	PHASE3	ACTIVE_NOT_RECRUITING	A Study Comparing Haploidentical Hematopoietic Stem Cell Transplantations (HSCTs) From Young Non-first-degree and Older First-degree Donors in Hematological Malignancies
NCT04708054	PHASE2/PHASE3	RECRUITING	Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS
NCT05153226	PHASE3	ACTIVE_NOT_RECRUITING	GvHD Prophylaxis in Unrelated Donor HCT: Randomized Trial Comparing PTCY Versus ATG
NCT05181592	PHASE3	ACTIVE_NOT_RECRUITING	Assessment of Effectiveness and Safety of Luspatercept in Patients Suffering From Lower-risk Myelodysplastic Syndrome.
NCT05316701	PHASE3	ACTIVE_NOT_RECRUITING	Precision-T: A Randomized Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies
NCT05457556	PHASE3	ACTIVE_NOT_RECRUITING	Mismatched Related Donor Versus Matched Unrelated Donor Stem Cell Transplantation for Children, Adolescents, and Young Adults With Acute Leukemia or Myelodysplastic Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYCLOPHOSPHAMIDE ANHYDROUS	4	163
AZACITIDINE	4	36
DECITABINE	4	36
BUSULFAN	4	31
DEFERASIROX	4	20
THIOTEPA	4	15
LUSPATERCEPT	4	14
FLUDARABINE PHOSPHATE	4	13
IDARUBICIN	4	13
CYTARABINE	4	12
DAUNORUBICIN HYDROCHLORIDE	4	12
MITOXANTRONE HYDROCHLORIDE	4	11
ETOPOSIDE	4	9
FILGRASTIM	4	8
MELPHALAN	4	7
ASPARAGINASE	4	6
THIOGUANINE	4	6
POSACONAZOLE	4	5
ALDESLEUKIN	4	4
LENALIDOMIDE	4	4
DEXTROMETHORPHAN	4	3
EPOETIN BETA	4	3
HYDROCORTISONE	4	3
ROXADUSTAT	4	2
AMPHOTERICIN B	4	1
AMSACRINE	4	1
CYCLOSPORINE	4	1
EPOETIN ZETA	4	1
MICAFUNGIN	4	1
MORPHINE SULFATE	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items; also 22 prognostic, 2 oncogenic, 1 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
TP53 Mutation	Azacitidine + Eprenetapopt	Sensitivity/Response	CIViC B	EID12029