Acute promyelocytic leukemia

Summary

Acute promyelocytic leukemia (MONDO:0012883) is a cancer with 7 cohort genes (5 CIViC-evidence somatic drivers; 3 ClinVar predisposition records) and 51 clinical trials. Molecularly, PML::RARA Fusion confers sensitivity to Arsenic Trioxide + Tretinoin in Acute Promyelocytic Leukemia (CIViC Level A); 11 further subtype–drug associations are mapped below. Top therapeutic interventions include arsenic trioxide, tretinoin, and idarubicin.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 7
• ClinVar variants: 3
• Phenotypes (HPO): 36
• Clinical trials: 51
• Precision-medicine evidence (CIViC): 12 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.11	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.28	United States	Validated
Annual incidence	1-9 / 1 000 000	0.3	France	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000225	Gingival bleeding	Frequent (30-79%)
HP:0000421	Epistaxis	Frequent (30-79%)
HP:0000967	Petechiae	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0000979	Purpura	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001876	Pancytopenia	Frequent (30-79%)
HP:0001882	Leukopenia	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0002875	Exertional dyspnea	Frequent (30-79%)
HP:0005521	Disseminated intravascular coagulation	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0031020	Bone marrow hypercellularity	Frequent (30-79%)
HP:0031035	Chronic infection	Frequent (30-79%)
HP:0031364	Ecchymosis	Frequent (30-79%)
HP:0000212	Gingival overgrowth	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001974	Leukocytosis	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002653	Bone pain	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0010280	Stomatitis	Occasional (5-29%)
HP:0011900	Hypofibrinogenemia	Occasional (5-29%)
HP:0025420	Diffuse alveolar hemorrhage	Occasional (5-29%)
HP:0030140	Oral cavity bleeding	Occasional (5-29%)
HP:0030955	Alcoholism	Occasional (5-29%)
HP:0031245	Productive cough	Occasional (5-29%)
HP:0000790	Hematuria	Very rare (<1-4%)
HP:0100608	Metrorrhagia	Very rare (<1-4%)
HP:0100758	Gangrene	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acute promyelocytic leukemia
Mondo ID	MONDO:0012883
EFO	EFO:0000224
MeSH	D015473
OMIM	612376
Orphanet	520
DOID	DOID:0060318, DOID:0081081
ICD-10-CM	C92.4
NCIT	C3182
SNOMED CT	110004001
UMLS	C0023487
MedGen	44127
GARD	0000538
MedDRA	10001019
NORD	2003
Is cancer (heuristic)	yes

Also known as: acute myeloblastic leukaemia 3 · acute myeloblastic leukemia 3 · acute myeloid leukaemia with t(15;17)(q22;q12);(PML/RARalpha) and variants · acute myeloid leukemia with t(15;17)(q22;q12);(PML/RARalpha) and variants · acute promyelocytic leukaemia with PML-rara · acute promyelocytic leukaemia with t(15;17)(q22;q12); PML-rara · acute promyelocytic leukaemia with t(15;17)(q22;q12); PML/rara · acute promyelocytic leukemia · acute promyelocytic leukemia with PML-rara · acute promyelocytic leukemia with t(15;17)(q22;q12); PML-rara · acute promyelocytic leukemia with t(15;17)(q22;q12); PML/rara · AML M3 · AML with t(15;17)(q22;q12) · AML with t(15;17)(q22;q12);(PML/RARalpha) and variants · APL · APML · APML - acute promyelocytic leukaemia · APML - acute promyelocytic leukemia · FAB M3 · leukemia, acute promyelocytic, somatic (+2 more)

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record · 24 cell lines.

Disease family

Classification path: disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › hematopoietic and lymphoid cell neoplasm › leukemia › myeloid leukemia › acute myeloid leukemia › inherited acute myeloid leukemia › acute promyelocytic leukemia

Related subtypes (2): mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2), mixed phenotype acute leukemia with t(v;11q23.3)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

2 benign/likely benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
577335	NM_017849.4(TMEM127):c.31G>T (p.Gly11Cys)	LOC129934333	Uncertain significance	criteria provided, multiple submitters, no conflicts
790646	NM_006185.4(NUMA1):c.5285G>A (p.Arg1762His)	IL18BP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
790647	NM_006185.4(NUMA1):c.2937T>C (p.Asn979=)	NUMA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 32 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
CDKN2B			CIViC #916
FLT3	Act	ALL,AML	CIViC #24
KIT	Act	AML,GIST,MEL,MGCT	CIViC #29
PML	LoF	LUNG	CIViC #39
NUMA1	LoF	BRCA,ESCA

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
RARA	No Known Disease Relationship	Autosomal dominant	acute promyelocytic leukemia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDKN2B	Orphanet:618	Familial melanoma
CDKN2B	Orphanet:652	Multiple endocrine neoplasia type 1
FLT3	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
FLT3	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
FLT3	Orphanet:589534	Mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2)
FLT3	Orphanet:589595	Mixed phenotype acute leukemia with t(v;11q23.3)
FLT3	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
FLT3	Orphanet:98832	Acute myeloid leukemia with minimal differentiation
FLT3	Orphanet:98833	Acute myeloblastic leukemia without maturation
FLT3	Orphanet:98834	Acute myeloblastic leukemia with maturation
FLT3	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
KIT	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
KIT	Orphanet:158766	Typical urticaria pigmentosa
KIT	Orphanet:158769	Plaque-form urticaria pigmentosa
KIT	Orphanet:158772	Nodular urticaria pigmentosa
KIT	Orphanet:158775	Smoldering systemic mastocytosis
KIT	Orphanet:158778	Isolated bone marrow mastocytosis
KIT	Orphanet:280785	Bullous diffuse cutaneous mastocytosis
KIT	Orphanet:280794	Pseudoxanthomatous diffuse cutaneous mastocytosis
KIT	Orphanet:2884	Piebaldism
KIT	Orphanet:44890	Gastrointestinal stromal tumor
KIT	Orphanet:566393	Acute mast cell leukemia
KIT	Orphanet:566396	Chronic mast cell leukemia
KIT	Orphanet:79455	Cutaneous mastocytoma
KIT	Orphanet:842	Testicular seminomatous germ cell tumor
KIT	Orphanet:90389	Telangiectasia macularis eruptiva perstans
KIT	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
KIT	Orphanet:98834	Acute myeloblastic leukemia with maturation
KIT	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
PML	Orphanet:520	Acute promyelocytic leukemia
RARA	Orphanet:520	Acute promyelocytic leukemia
NUMA1	Orphanet:520	Acute promyelocytic leukemia

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	4
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDKN2B	HGNC:1788	ENSG00000147883	P42772	Cyclin-dependent kinase 4 inhibitor B	civic_evidence
FLT3	HGNC:3765	ENSG00000122025	P36888	Receptor-type tyrosine-protein kinase FLT3	civic_evidence
KIT	HGNC:6342	ENSG00000157404	P10721	Mast/stem cell growth factor receptor Kit	civic_evidence
PML	HGNC:9113	ENSG00000140464	P29590	Protein PML	civic_evidence
RARA	HGNC:9864	ENSG00000131759	P10276	Retinoic acid receptor alpha	gencc
IL18BP	HGNC:5987	ENSG00000137496	O95998	Interleukin-18-binding protein	clinvar
NUMA1	HGNC:8059	ENSG00000137497	Q14980	Nuclear mitotic apparatus protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDKN2B	Cyclin-dependent kinase 4 inhibitor B	Interacts strongly with CDK4 and CDK6.
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.
KIT	Mast/stem cell growth factor receptor Kit	Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell develo…
PML	Protein PML	Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechani…
RARA	Retinoic acid receptor alpha	Receptor for retinoic acid.
IL18BP	Interleukin-18-binding protein	Isoform A binds to IL-18 and inhibits its activity.
NUMA1	Nuclear mitotic apparatus protein 1	Microtubule (MT)-binding protein that plays a role in the formation and maintenance of the spindle poles and the alignement and the segregation of chromosomes during mitotic cell division.

Protein-family classification

Druggable: 4 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.57

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
Nuclear receptor	1	55.1×	0.073
Kinase	2	7.9×	0.073
Antibody/Immunoglobulin	1	4.2×	0.433
Scaffold/PPI	1	2.5×	0.512
Transcription factor	1	1.2×	0.714
Other/Unknown	1	0.3×	0.997

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDKN2B	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor
FLT3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
KIT	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
PML	Transcription factor	no		Znf_B-box, Znf_RING, Znf_RING/FYVE/PHD
RARA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
IL18BP	Antibody/Immunoglobulin	yes		Ig-like_dom, Ig-like_fold, Ig-like_dom_sf
NUMA1	Other/Unknown	no		NuMA_N_HOOK, NuMA_LGNBD, MT-Golgi_org_protein

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of uterus	2
granulocyte	2
colonic mucosa	1
jejunal mucosa	1
lower esophagus mucosa	1
cerebellar cortex	1
cerebellar hemisphere	1
male germ line stem cell (sensu Vertebrata) in testis	1
lateral nuclear group of thalamus	1
oocyte	1
secondary oocyte	1
omental fat pad	1
peritoneum	1
mammary duct	1
monocyte	1
spleen	1
upper lobe of left lung	1
endocervix	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDKN2B	219	ubiquitous	marker	jejunal mucosa, colonic mucosa, lower esophagus mucosa
FLT3	166	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere, cerebellar cortex
KIT	263	broad	marker	lateral nuclear group of thalamus, secondary oocyte, oocyte
PML	253	ubiquitous	marker	omental fat pad, peritoneum, body of uterus
RARA	276	ubiquitous	marker	mammary duct, monocyte, granulocyte
IL18BP	185	ubiquitous	marker	spleen, upper lobe of left lung, granulocyte
NUMA1	294	ubiquitous	marker	right uterine tube, body of uterus, endocervix

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIT	6,087
NUMA1	4,282
RARA	3,885
PML	3,704
FLT3	3,570
CDKN2B	3,431
IL18BP	849

Intra-cohort edges

A	B	Sources
NUMA1	RARA	string_interaction
PML	RARA	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIT	P10721	52
PML	P29590	20
RARA	P10276	14
FLT3	P36888	11
NUMA1	Q14980	5
IL18BP	O95998	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDKN2B	P42772	90.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 95. Enrichment computed across 7 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dasatinib-resistant KIT mutants	1	1631.4×	0.002	KIT
Imatinib-resistant KIT mutants	1	1631.4×	0.002	KIT
KIT mutants bind TKIs	1	1631.4×	0.002	KIT
Masitinib-resistant KIT mutants	1	1631.4×	0.002	KIT
Nilotinib-resistant KIT mutants	1	1631.4×	0.002	KIT
Regorafenib-resistant KIT mutants	1	1631.4×	0.002	KIT
Signaling by kinase domain mutants of KIT	1	1631.4×	0.002	KIT
Sunitinib-resistant KIT mutants	1	1631.4×	0.002	KIT
Signaling by juxtamembrane domain KIT mutants	1	1631.4×	0.002	KIT
Sorafenib-resistant KIT mutants	1	1631.4×	0.002	KIT
Drug resistance of KIT mutants	1	1631.4×	0.002	KIT
Signaling by extracellular domain mutants of KIT	1	1631.4×	0.002	KIT
FLT3 mutants bind TKIs	1	1631.4×	0.002	FLT3
KW2449-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
semaxanib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
crenolanib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
gilteritinib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
lestaurtinib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
midostaurin-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
pexidartinib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
ponatinib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
quizartinib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
sorafenib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
sunitinib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
tandutinib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
linifanib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
tamatinib-resistant FLT3 mutants	1	1631.4×	0.002	FLT3
Constitutive Signaling by Aberrant PI3K in Cancer	2	36.2×	0.004	FLT3, KIT
Transcriptional regulation of granulopoiesis	2	35.9×	0.004	PML, RARA
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	27.6×	0.007	FLT3, KIT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
myeloid progenitor cell differentiation	2	687.8×	7e-04	FLT3, KIT
positive regulation of tyrosine phosphorylation of STAT protein	2	209.3×	0.004	FLT3, KIT
retinoic acid receptor signaling pathway	2	185.2×	0.004	PML, RARA
regulation of calcium ion transport into cytosol	1	2407.4×	0.006	PML
negative regulation of translation in response to oxidative stress	1	2407.4×	0.006	PML
anastral spindle assembly	1	2407.4×	0.006	NUMA1
Sertoli cell fate commitment	1	2407.4×	0.006	RARA
melanocyte adhesion	1	2407.4×	0.006	KIT
positive regulation of pyloric antrum smooth muscle contraction	1	2407.4×	0.006	KIT
positive regulation of protein localization to spindle pole body	1	2407.4×	0.006	NUMA1
positive regulation of mitotic spindle elongation	1	2407.4×	0.006	NUMA1
positive regulation of colon smooth muscle contraction	1	2407.4×	0.006	KIT
response to cytokine	2	107.0×	0.006	PML, RARA
cellular senescence	2	84.5×	0.006	CDKN2B, PML
hemopoiesis	2	76.4×	0.006	FLT3, KIT
B cell differentiation	2	62.5×	0.006	FLT3, KIT
negative regulation of cell population proliferation	3	18.1×	0.006	CDKN2B, PML, RARA
positive regulation of binding	1	1203.7×	0.009	RARA
positive regulation of vascular associated smooth muscle cell differentiation	1	1203.7×	0.009	KIT
transforming growth factor beta receptor signaling pathway	2	45.4×	0.009	CDKN2B, PML
positive regulation of cell population proliferation	3	14.4×	0.009	FLT3, KIT, RARA
leukocyte homeostasis	1	802.5×	0.009	FLT3
Fc receptor signaling pathway	1	802.5×	0.009	KIT
Kit signaling pathway	1	802.5×	0.009	KIT
melanocyte migration	1	802.5×	0.009	KIT
obsolete regulation of bile acid metabolic process	1	802.5×	0.009	KIT
positive regulation of small intestine smooth muscle contraction	1	802.5×	0.009	KIT
positive regulation of protein localization to chromosome, telomeric region	1	802.5×	0.009	PML
protein autophosphorylation	2	41.5×	0.009	FLT3, KIT
cytokine-mediated signaling pathway	2	37.3×	0.009	FLT3, KIT

Therapeutics

Drugs indicated for this disease

2 approved, 6 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Arsenic Trioxide	Approved (phase 4)
Tretinoin	Approved (phase 4)
Cytarabine	Phase 3 (in late-stage trials)
Hydroxyurea	Phase 3 (in late-stage trials)
Idarubicin	Phase 3 (in late-stage trials)
Indigo	Phase 3 (in late-stage trials)
Methotrexate	Phase 3 (in late-stage trials)
Mitoxantrone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Ascorbic Acid, Bortezomib, Gelatin, Gemtuzumab Ozogamicin, Romidepsin, Tamibarotene, Tucidinostat, Venetoclax.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 5 · Undrugged: 2

Druggability breadth: 5 of 7 evidence-associated genes (71%) 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
FLT3	PONATINIB
KIT	PONATINIB
RARA	BEXAROTENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLT3	143	4
KIT	99	4
RARA	11	4
PML	1	2
NUMA1	1	2
CDKN2B	0	0
IL18BP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FLT3, KIT
AFATINIB	4	FLT3
FEDRATINIB	4	FLT3, KIT
TIVOZANIB	4	FLT3, KIT
AXITINIB	4	FLT3, KIT
SORAFENIB	4	FLT3, KIT
NERATINIB	4	FLT3
INFIGRATINIB PHOSPHATE	4	FLT3, KIT
INFIGRATINIB	4	FLT3, KIT
IBRUTINIB	4	FLT3
PALBOCICLIB	4	FLT3
REGORAFENIB	4	FLT3, KIT
ENTRECTINIB	4	FLT3, KIT
PACRITINIB	4	FLT3
FOSTAMATINIB	4	FLT3
QUIZARTINIB DIHYDROCHLORIDE	4	FLT3
CABOZANTINIB	4	FLT3, KIT
CERITINIB	4	FLT3, KIT
VANDETANIB	4	FLT3, KIT
NILOTINIB	4	FLT3, KIT
BOSUTINIB	4	FLT3, KIT
FILGOTINIB	4	FLT3
ABEMACICLIB	4	FLT3
GILTERITINIB	4	FLT3
BRIGATINIB	4	FLT3, KIT
PEXIDARTINIB	4	FLT3, KIT
PRALSETINIB	4	FLT3
PAZOPANIB	4	FLT3, KIT
NINTEDANIB	4	FLT3, KIT
SUNITINIB	4	FLT3, KIT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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
KIT	2,305	Binding:2242, ADMET:32, Functional:22, Toxicity:9
RARA	368	Binding:279, Functional:85, ADMET:4
PML	34	Binding:34
NUMA1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FLT3	2.7.10.1	receptor protein-tyrosine kinase
KIT	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FLT3	3,132
KIT	2,305
RARA	368

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

29 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	FLT3, KIT
AFATINIB	4	FLT3
FEDRATINIB	4	FLT3, KIT
TIVOZANIB	4	FLT3, KIT
AXITINIB	4	FLT3, KIT
NERATINIB	4	FLT3
INFIGRATINIB PHOSPHATE	4	FLT3, KIT
INFIGRATINIB	4	FLT3, KIT
IBRUTINIB	4	FLT3
PALBOCICLIB	4	FLT3
REGORAFENIB	4	FLT3, KIT
ENTRECTINIB	4	FLT3, KIT
PACRITINIB	4	FLT3
FOSTAMATINIB	4	FLT3
QUIZARTINIB DIHYDROCHLORIDE	4	FLT3
CABOZANTINIB	4	FLT3, KIT
CERITINIB	4	FLT3, KIT
VANDETANIB	4	FLT3, KIT
NILOTINIB	4	FLT3, KIT
BOSUTINIB	4	FLT3, KIT
FILGOTINIB	4	FLT3
ABEMACICLIB	4	FLT3
GILTERITINIB	4	FLT3
BRIGATINIB	4	FLT3, KIT
PEXIDARTINIB	4	FLT3, KIT
PRALSETINIB	4	FLT3
PAZOPANIB	4	FLT3, KIT
NINTEDANIB	4	FLT3, KIT
SUNITINIB	4	FLT3, KIT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	FLT3, KIT, RARA
B	Phased (≥1) drug, not yet approved	2	PML, NUMA1
C	Druggable family + PDB, no drug	1	IL18BP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CDKN2B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDKN2B	0	—
IL18BP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 51.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	14
Not specified	13
PHASE3	7
PHASE1	7
PHASE4	6
PHASE2/PHASE3	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00196768	PHASE4	UNKNOWN	Treatment Protocol for Relapsed Acute Promyelocytic Leukemia (APL) With Arsenic
NCT00408278	PHASE4	COMPLETED	Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia (PETHEMA LPA 2005)
NCT00465933	PHASE4	COMPLETED	Treatment of Acute Promyelocytic Leukemia With All-Trans Retinoic Acid (ATRA) and Idarubicin (AIDA)
NCT00504764	PHASE4	COMPLETED	Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
NCT01987297	PHASE4	UNKNOWN	Combined Retinoic Acid,Arsenic Trioxide and Chemo for Newly-diagnosed APL
NCT02020161	PHASE4	UNKNOWN	Clinical Guidelines for APL Treatment
NCT06544109	PHASE2/PHASE3	ENROLLING_BY_INVITATION	Venetoclax for Prevention of Differentiation Syndrom in Acute Promyelocytic Leukemia Patients
NCT07296445	PHASE3	NOT_YET_RECRUITING	A Trial to Investigate Whether Oral Arsenic Trioxide Is Similar to Intravenous Arsenic Trioxide in Pharmacokinetics, Safety, and Efficacy (LATITUDE/SDKARS-301)
NCT07503730	PHASE3	RECRUITING	Early Use of Realgar-Indigo Naturalis Formula (RIF) Combined With All-trans Retinoic Acid (ATRA) for Treating Acute Promyelocytic Leukemia (APL).
NCT07504458	PHASE3	RECRUITING	Pivotal Open-label Phase 3 Clinical Study of QTX-2101 in Adult Patients With Acute Promyelocytic Leukemia
NCT07597941	PHASE2/PHASE3	NOT_YET_RECRUITING	Lisaftoclax for Prevention of Differentiation Syndrom in Acute Promyelocytic Leukemia Patients
NCT00517712	PHASE2/PHASE3	UNKNOWN	Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia
NCT01226303	PHASE3	UNKNOWN	Treatment Study for Children and Adolescents With Acute Promyelocitic Leukemia
NCT02688140	PHASE3	COMPLETED	Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia
NCT02899169	PHASE3	UNKNOWN	Treatment of Non-high-risk Acute Promyelocytic Leukemia (APL) With Realgar-Indigo Naturalis Formula (RIF)
NCT04175587	PHASE3	UNKNOWN	Randomized,International Multi-center Clinical Trial of RIF Plus RA for Non-high-risk APL
NCT01409161	PHASE2	RECRUITING	Tretinoin and Arsenic Trioxide With or Without Gemtuzumab Ozogamicin in Treating Patients With Previously Untreated Acute Promyelocytic Leukemia
NCT04687176	PHASE2	RECRUITING	Frontline Oral Arsenic Trioxide for APL
NCT04793919	PHASE2	RECRUITING	Treatment Study for Children and Adolescents With Acute Promyelocytic Leukemia
NCT05881265	PHASE2	RECRUITING	Treatment of Chidamide and Venetoclax for Retinoic Acid and Arsenic Resistant Acute Promyelocytic Leukemia
NCT06982274	PHASE2	RECRUITING	Oral Arsenic With ATRA for Newly Diagnosed Patients With Acute Promyelocytic Leukemia
NCT00413166	PHASE2	COMPLETED	All-trans Retinoic Acid, and Arsenic +/- Idarubicin
NCT00520208	PHASE2	COMPLETED	Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL
NCT00670150	PHASE2	WITHDRAWN	New Retinoid Agent Combined With Arsenic Trioxide for Untreated Acute Promyelocytic Leukemia
NCT00675870	PHASE2	UNKNOWN	Study of NRX 195183 Therapy for Patients With Relapsed or Refractory Acute Promyelocytic Leukemia
NCT00907582	PHASE2	TERMINATED	ASCT for Relapsed APL After Molecular Remission
NCT01064570	PHASE2	UNKNOWN	AIDA 2000 Guidelines
NCT01253070	PHASE2	COMPLETED	Sorafenib Tosylate and Chemotherapy in Treating Older Patients With Acute Myeloid Leukemia
NCT01404949	PHASE2	COMPLETED	Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
NCT03624270	PHASE2	UNKNOWN	Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia
NCT05497310	PHASE1/PHASE2	UNKNOWN	Effectiveness and Safety of Therapy Based on Attenuated ATO Plus Low-Dose ATRA in Patients With APL
NCT02390635	PHASE1	RECRUITING	PET/MRI, 18F-FDG PET/CT and Whole Body MRI in Finding Extramedullary Myeloid Leukemia in Patients With Newly Diagnosed Acute Myeloid Leukemia
NCT00852709	PHASE1	TERMINATED	Phase I Dose-Escalation Trial of Clofarabine Followed by Escalating Doses of Fractionated Cyclophosphamide in Children With Relapsed or Refractory Acute Leukemias
NCT00985530	PHASE1	TERMINATED	Tamibarotene and Arsenic Trioxide for Relapsed Acute Promyelocytic Leukemia
NCT01902329	PHASE1	COMPLETED	A Safety Study of SGN-CD33A in AML Patients
NCT02086773	PHASE1	COMPLETED	Red Cell Transfusion Goals in Patients With Acute Leukemias
NCT04996030	PHASE1	SUSPENDED	A Study for Oral SY-2101 for Participants With Acute Promyelocytic Leukemia
NCT06882031	PHASE1	COMPLETED	Evaluate the Pharmacokinetics of Oral Arsenic Trioxide Solution Under Fasting and Fed Conditions, to Compare Intravenous Arsenic Trioxide, in Acute Promyelocytic Leukemia
NCT00003861	Not specified	ACTIVE_NOT_RECRUITING	Diagnostic Study of Patients With Acute Lymphoblastic Leukemia or Acute Promyelocytic Leukemia
NCT02938858	Not specified	ACTIVE_NOT_RECRUITING	French Registry of First-line Treatment of Acute Promyelocytic Leukemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ARSENIC TRIOXIDE	4	12
TRETINOIN	4	11
IDARUBICIN	4	4
GEMTUZUMAB OZOGAMICIN	4	3
MERCAPTOPURINE ANHYDROUS	4	3
MITOXANTRONE	4	2
TAMIBAROTENE	4	2
CYTARABINE	4	1
HYDROXYUREA	4	1
METHOTREXATE	4	1
RIFAMPIN	4	1
SORAFENIB	4	1
VENETOCLAX	4	1
APG-2575	2	1
ARSENIC	2	1
GADOLINIUM	2	1
VADASTUXIMAB TALIRINE	2	1
CHEMBL426	0	1
CHEMBL3970001	0	1
CHEMBL5567397	0	1
CHEMBL4087968	0	1
HMA	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 12 predictive associations from 13 curated evidence items; also 8 diagnostic, 3 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
PML::RARA Fusion	Arsenic Trioxide + Tretinoin	Sensitivity/Response	CIViC A	EID1091
PML::RARA Fusion	Tretinoin	Sensitivity/Response	CIViC B	EID316 +1
PML::RARA Fusion	Gemtuzumab Ozogamicin	Sensitivity/Response	CIViC B	EID8300
FLT3 ITD	Anthracycline Antineoplastic Antibiotic + Tretinoin	Resistance	CIViC B	EID1112
PML B2 DOMAIN MUTATION	Tretinoin	Resistance	CIViC B	EID1092
PML::RARA Fusion AND PML A216T	Arsenic Trioxide	Resistance	CIViC B	EID8179
PML::RARA Fusion AND PML A216V	Arsenic Trioxide	Resistance	CIViC B	EID8177
PML::RARA Fusion AND PML S214L	Arsenic Trioxide	Resistance	CIViC B	EID8178
PML K227_T233del	Tamibarotene + Tretinoin	Resistance	CIViC C	EID8175
PML::RARA Fusion AND PML A216V	Tretinoin	Resistance	CIViC C	EID1093
PML::RARA Fusion AND PML L218P	Tretinoin	Resistance	CIViC C	EID1094
KIT Mutation	Nilotinib	Sensitivity/Response	CIViC D	EID5573