Juvenile myelomonocytic leukemia

Summary

Juvenile myelomonocytic leukemia (MONDO:0011908) is a cancer caused by CBL (GenCC Strong), with 10 cohort genes (7 CIViC-evidence somatic drivers; 1,220 ClinVar predisposition records) and 286 clinical trials. The dominant Reactome pathway is FLT3 Signaling (5 cohort genes). Molecularly, ZMIZ1::ABL1 Fusion confers sensitivity to Azacitidine + Dasatinib in Chronic Myelomonocytic Leukemia (CIViC Level C). Top therapeutic interventions include cyclophosphamide anhydrous, clofarabine, and decitabine.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: CBL (GenCC Strong)
• Cohort genes: 10
• ClinVar variants: 1,220
• Clinical trials: 286
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	juvenile myelomonocytic leukemia
Mondo ID	MONDO:0011908
EFO	EFO:1000309
MeSH	D054429
OMIM	607785
Orphanet	86834
DOID	DOID:0050458
ICD-10-CM	C93.3
ICD-11	1786015803
NCIT	C9233
SNOMED CT	445227008
UMLS	C0349639
MedGen	138109
GARD	0009884
MedDRA	10023249
NORD	1316
Is cancer (heuristic)	yes

Also known as: chronic myelomonocytic leukaemia · chronic myelomonocytic leukemia · JCML · JMML · juvenile chronic myelogenous leukaemia · juvenile chronic myelogenous leukemia · juvenile chronic myeloid leukaemia · juvenile chronic myeloid leukemia · juvenile chronic myelomonocytic leukaemia · juvenile chronic myelomonocytic leukemia · juvenile myelomonocytic leukemia · juvenile myelomonocytic leukemia, autosomal dominant, somatic mutation · leukemia, juvenile myelomonocytic, autosomal dominant, somatic mutation · leukemia, juvenile myelomonocytic, somatic

Data availability: 1,220 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › hematopoietic and lymphoid cell neoplasm › leukemia › chronic leukemia › chronic myelomonocytic leukemia › juvenile myelomonocytic leukemia

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

600 retrieved; paginated sample, class counts are floors:

194 conflicting classifications of pathogenicity, 192 uncertain significance, 61 pathogenic, 48 likely benign, 48 pathogenic/likely pathogenic, 31 benign/likely benign, 20 likely pathogenic, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13811	NM_005188.4(CBL):c.1111T>C (p.Tyr371His)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177959	NM_005188.4(CBL):c.1228-2A>G	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29824	NM_005188.4(CBL):c.1112A>G (p.Tyr371Cys)	CBL	Pathogenic	criteria provided, multiple submitters, no conflicts
12580	NM_004985.5(KRAS):c.38G>A (p.Gly13Asp)	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12582	NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12583	NM_004985.5(KRAS):c.35G>T (p.Gly12Val)	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12584	NM_004985.5(KRAS):c.34G>A (p.Gly12Ser)	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1069238	NM_001042492.3(NF1):c.60+2T>C	LOC111811965	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186896	NM_001042492.3(NF1):c.55G>T (p.Glu19Ter)	LOC111811965	Pathogenic	criteria provided, multiple submitters, no conflicts
2736490	NM_001042492.3(NF1):c.3G>T (p.Met1Ile)	LOC111811965	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1036158	NM_001042492.3(NF1):c.3586C>T (p.Leu1196Phe)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048716	NM_001042492.3(NF1):c.4986G>A (p.Trp1662Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1048718	NM_001042492.3(NF1):c.5652T>G (p.Phe1884Leu)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068536	NM_001042492.3(NF1):c.2294del (p.Arg765fs)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069722	NM_001042492.3(NF1):c.3628G>T (p.Glu1210Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070937	NM_001042492.3(NF1):c.5585T>G (p.Leu1862Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072070	NM_001042492.3(NF1):c.5158del (p.Glu1720fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1072273	NM_001042492.3(NF1):c.5812+2T>G	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073116	NM_001042492.3(NF1):c.731-1G>C	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1333529	NM_001042492.3(NF1):c.5167C>T (p.Gln1723Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1360877	NM_001042492.3(NF1):c.4980dup (p.Lys1661Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387584	NM_001042492.3(NF1):c.4760del (p.Ala1586_Leu1587insTer)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141513	NM_001042492.3(NF1):c.2033dup (p.Ile679fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1421501	NM_001042492.3(NF1):c.7158dup (p.Asn2387Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1421521	NM_001042492.3(NF1):c.4515del (p.Ala1506fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1435680	NM_001042492.3(NF1):c.7145del (p.Phe2382fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1453712	NM_001042492.3(NF1):c.2851-1G>C	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460161	NM_001042492.3(NF1):c.289-2A>G	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1527847	NM_001042492.3(NF1):c.6897del (p.Lys2300fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1749687	NM_001042492.3(NF1):c.5861C>A (p.Ser1954Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 42 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
CBL	LoF	ALL,AML,ESCA	CIViC #778
KRAS	Act	ALL,AML,ANSC,BLADDER,BLCA,BRCA,CEAD,CESC,CHOL,CLLSLL,COAD,COADREAD,DLBCLNOS,EGC,ESCA,ESCC,HCC,LUAD,LUSC,MEL,MGCT,MT,NSCLC,OVT,PAAD,PANCREAS,PAST,PCM,PRAD,PRCC,READ,STAD,STOMACH,UCEC,UCS,WDTC	CIViC #30
ASXL1	LoF	AML,BLCA,BRCA,CCRCC,CHOL,CLLSLL,COAD,ESCA,HGGNOS,HNSC,MBL,PAST,PRAD,STOMACH	CIViC #68
SH2B3	Act	MDS	CIViC #7954
NF1	LoF	ACC,ALL,AML,ANGS,BLCA,BRCA,CCRCC,CHOL,CLLSLL,COADREAD,GB,GBM,GIST,HCC,HNSC,LGGNOS,LMS,LUAD,LUNG,LUSC,MEL,NBL,NSCLC,OVT,PAST,PGNG,PLMESO,RMS,SKCM,SOFT_TISSUE,STAD,THYM,UCS	CIViC #3867
NRAS	Act	ALL,AML,ANGS,CHOL,CLLSLL,COAD,COADREAD,GBM,HCC,LGGNOS,LUAD,LUSC,MEL,MGCT,NPC,OVT,PCM,PROSTATE,SKCM,THYM,UCEC,WDTC	CIViC #36
PTPN11	Act	ALL,AML,CLLSLL,COADREAD,GBM,LGGNOS,NBL,PAST,PCM	CIViC #4685

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
CBL	Strong	Autosomal dominant	juvenile myelomonocytic leukemia	8
ARHGAP26	No Known Disease Relationship	Unknown	juvenile myelomonocytic leukemia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CBL	Orphanet:363972	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia
CBL	Orphanet:648	Noonan syndrome
CBL	Orphanet:86834	Juvenile myelomonocytic leukemia
CBL	Orphanet:98850	Aggressive systemic mastocytosis
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
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
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma
NRAS	Orphanet:146	Differentiated thyroid carcinoma
NRAS	Orphanet:2612	Linear nevus sebaceus syndrome
NRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
NRAS	Orphanet:389	Langerhans cell histiocytosis
NRAS	Orphanet:626	Large/giant congenital melanocytic nevus
NRAS	Orphanet:648	Noonan syndrome
NRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

10 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CBL	HGNC:1541	ENSG00000110395	P22681	E3 ubiquitin-protein ligase CBL	gencc,clinvar,civic_evidence
ARHGAP26	HGNC:17073	ENSG00000145819	Q9UNA1	Rho GTPase-activating protein 26	gencc,clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar,civic_evidence
ASXL1	HGNC:18318	ENSG00000171456	Q8IXJ9	Polycomb group protein ASXL1	clinvar
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	clinvar
EVI2A	HGNC:3499	ENSG00000126860	P22794	Protein EVI2A	clinvar
FRA11B	HGNC:3837			fragile site, folic acid type, rare, fra(11)(q23.3)	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CBL	E3 ubiquitin-protein ligase CBL	E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors.
ARHGAP26	Rho GTPase-activating protein 26	GTPase-activating protein for RHOA and CDC42.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
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).
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
EVI2A	Protein EVI2A	May complex with itself or/and other proteins within the membrane, to function as part of a cell-surface receptor.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 5 · Druggable fraction: 0.2

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
Phosphatase	1	8.4×	0.283
Scaffold/PPI	2	3.5×	0.283
Enzyme (other)	1	1.2×	0.756
Other/Unknown	5	0.9×	0.756
Transcription factor	1	0.8×	0.756

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CBL	Transcription factor	no	2.3.2.27	Znf_RING, Adaptor_Cbl_N_hlx, UBA-like_sf
ARHGAP26	Scaffold/PPI	no		RhoGAP_dom, SH3_domain, PH_domain
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
ASXL1	Other/Unknown	no		Asxl_HARE-HTH, ASX/ASX-like, ASX-like_PHD
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
EVI2A	Other/Unknown	no		Ectropic_vir_integratn_site_2A
FRA11B	Other/Unknown	no
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 1.

9 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)	9
unknown	1

Top tissues across cohort

Tissue	Cohort genes
trigeminal ganglion	2
colonic epithelium	2
sural nerve	2
adrenal tissue	2
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
blood	1
nipple	1
pylorus	1
sperm	1
leukocyte	1
monocyte	1
mononuclear cell	1
corpus callosum	1
endothelial cell	1
inferior vagus X ganglion	1
calcaneal tendon	1
epithelium of nasopharynx	1
gingival epithelium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CBL	271	ubiquitous	marker	primordial germ cell in gonad, trigeminal ganglion, male germ line stem cell (sensu Vertebrata) in testis
ARHGAP26	270	ubiquitous	marker	sural nerve, blood, colonic epithelium
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
ASXL1	294	ubiquitous	marker	sural nerve, sperm, adrenal tissue
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
EVI2A	260	ubiquitous	marker	corpus callosum, inferior vagus X ganglion, endothelial cell
FRA11B
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
NRAS	7,598
PTPN11	6,009
NF1	5,540
CBL	4,575
ASXL1	2,816
SH2B3	1,617
ARHGAP26	1,165
EVI2A	705
FRA11B	0

Intra-cohort edges

A	B	Sources
ARHGAP26	KRAS	string_interaction
ASXL1	SH2B3	string_interaction
EVI2A	NF1	biogrid_interaction, intact, string_interaction
KRAS	NF1	string_interaction
KRAS	NRAS	intact
NF1	NRAS	string_interaction
NF1	PTPN11	string_interaction
NRAS	PTPN11	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
PTPN11	Q06124	115
NRAS	P01111	35
CBL	P22681	33
NF1	P21359	26
ASXL1	Q8IXJ9	4
ARHGAP26	Q9UNA1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SH2B3	Q9UQQ2	63.45
EVI2A	P22794	56.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 170. Enrichment computed across 10 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FLT3 Signaling	5	216.3×	1e-09	CBL, KRAS, SH2B3, NRAS, PTPN11
Signaling by SCF-KIT	5	155.2×	4e-09	CBL, KRAS, SH2B3, NRAS, PTPN11
RAS signaling downstream of NF1 loss-of-function variants	3	611.8×	4e-07	KRAS, NF1, NRAS
Activated NTRK2 signals through FRS2 and FRS3	3	356.9×	2e-06	KRAS, NRAS, PTPN11
Signaling by FLT3 ITD and TKD mutants	3	285.5×	3e-06	KRAS, NRAS, PTPN11
Constitutive Signaling by EGFRvIII	3	267.7×	4e-06	CBL, KRAS, NRAS
Tie2 Signaling	3	225.4×	5e-06	KRAS, NRAS, PTPN11
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	3	214.1×	5e-06	CBL, KRAS, NRAS
FRS-mediated FGFR3 signaling	3	203.9×	6e-06	KRAS, NRAS, PTPN11
FRS-mediated FGFR4 signaling	3	186.2×	7e-06	KRAS, NRAS, PTPN11
FRS-mediated FGFR1 signaling	3	171.3×	8e-06	KRAS, NRAS, PTPN11
FRS-mediated FGFR2 signaling	3	164.7×	8e-06	KRAS, NRAS, PTPN11
Downstream signal transduction	3	142.8×	1e-05	KRAS, NRAS, PTPN11
Signaling by RAS GAP mutants	2	951.7×	1e-05	KRAS, NRAS
Signaling by RAS GTPase mutants	2	951.7×	1e-05	KRAS, NRAS
Signaling by CSF1 (M-CSF) in myeloid cells	3	129.8×	1e-05	CBL, KRAS, PTPN11
Activation of RAS in B cells	2	571.0×	4e-05	KRAS, NRAS
Regulation of RAS by GAPs	3	72.6×	7e-05	KRAS, NF1, NRAS
Estrogen-stimulated signaling through PRKCZ	2	407.9×	8e-05	KRAS, NRAS
SOS-mediated signalling	2	356.9×	1e-04	KRAS, NRAS
Activated NTRK3 signals through RAS	2	317.2×	1e-04	KRAS, NRAS
EGFR Transactivation by Gastrin	2	285.5×	1e-04	KRAS, NRAS
SHC-related events triggered by IGF1R	2	285.5×	1e-04	KRAS, NRAS
Activated NTRK2 signals through RAS	2	285.5×	1e-04	KRAS, NRAS
MET activates RAS signaling	2	259.6×	2e-04	KRAS, NRAS
Interleukin-6 signaling	2	237.9×	2e-04	CBL, PTPN11
Signaling by FGFR4 in disease	2	237.9×	2e-04	KRAS, NRAS
Constitutive Signaling by Overexpressed ERBB2	2	237.9×	2e-04	KRAS, NRAS
p38MAPK events	2	219.6×	2e-04	KRAS, NRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	2	219.6×	2e-04	KRAS, NRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
forebrain astrocyte development	2	1404.3×	1e-04	KRAS, NF1
Ras protein signal transduction	3	77.1×	7e-04	KRAS, NF1, NRAS
regulation of synaptic transmission, GABAergic	2	263.3×	0.001	KRAS, NF1
regulation of long-term neuronal synaptic plasticity	2	247.8×	0.001	KRAS, NF1
MAPK cascade	3	57.5×	0.001	KRAS, NF1, NRAS
cytokine-mediated signaling pathway	3	49.0×	0.001	CBL, KRAS, PTPN11
megakaryocyte development	2	175.5×	0.002	SH2B3, PTPN11
Rac protein signal transduction	2	140.4×	0.002	KRAS, NF1
negative regulation of T cell activation	2	131.7×	0.002	CBL, PTPN11
actin cytoskeleton organization	3	29.7×	0.002	ARHGAP26, KRAS, NF1
homeostasis of number of cells within a tissue	2	110.9×	0.003	KRAS, PTPN11
negative regulation of T cell receptor signaling pathway	2	91.6×	0.004	CBL, PTPN11
visual learning	2	76.6×	0.005	KRAS, NF1
negative regulation of MAPK cascade	2	75.2×	0.005	SH2B3, NF1
positive regulation of mast cell apoptotic process	1	2106.5×	0.006	NF1
regulation of glial cell differentiation	1	2106.5×	0.006	NF1
response to mineralocorticoid	1	2106.5×	0.006	KRAS
negative regulation of cortisol secretion	1	2106.5×	0.006	PTPN11
negative regulation of growth hormone secretion	1	2106.5×	0.006	PTPN11
observational learning	1	2106.5×	0.006	NF1
positive regulation of endothelial cell proliferation	2	57.7×	0.006	NF1, NRAS
liver development	2	55.4×	0.006	KRAS, NF1
microvillus organization	1	1053.2×	0.008	PTPN11
regulation of kidney size	1	1053.2×	0.008	ASXL1
gamma-aminobutyric acid secretion, neurotransmission	1	1053.2×	0.008	NF1
intestinal epithelial cell migration	1	1053.2×	0.008	PTPN11
negative regulation of Kit signaling pathway	1	1053.2×	0.008	SH2B3
neuron apoptotic process	2	46.3×	0.008	KRAS, NF1
Schwann cell proliferation	1	702.2×	0.009	NF1
cerebellar cortex formation	1	702.2×	0.009	PTPN11

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

9 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Busulfan	Phase 2
Cytarabine	Phase 2
Fludarabine Phosphate	Phase 2
Isotretinoin	Phase 2
Melphalan	Phase 2
Methotrexate	Phase 2
Mycophenolate Mofetil	Phase 2
Tacrolimus Anhydrous	Phase 2
Tipifarnib	Phase 2

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 7

Druggability breadth: 4 of 10 evidence-associated genes (40%) 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
KRAS	VEMURAFENIB
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRAS	11	4
PTPN11	8	4
NRAS	1	1
CBL	0	0
ARHGAP26	0	0
ASXL1	0	0
SH2B3	0	0
EVI2A	0	0
FRA11B	0	0
NF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
ESTRAMUSTINE PHOSPHATE	4	PTPN11
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS
L-778123 FREE BASE	1	NRAS
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
KRAS	861	Binding:829, Functional:32
PTPN11	588	Binding:585, Functional:2, ADMET:1
NRAS	18	Binding:18
CBL	4	Binding:2, Toxicity:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CBL	2.3.2.27	RING-type E3 ubiquitin transferase
KRAS	3.6.5.2	small monomeric GTPase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KRAS	861
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

20 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)
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
ESTRAMUSTINE PHOSPHATE	4	PTPN11
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS
L-778123 FREE BASE	1	NRAS
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KRAS, PTPN11
B	Phased (≥1) drug, not yet approved	1	NRAS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	CBL, ARHGAP26, ASXL1, SH2B3, EVI2A, FRA11B, NF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NF1	0	KRAS, NRAS
CBL	4	—
ARHGAP26	0	—
ASXL1	0	—
SH2B3	0	—
EVI2A	0	—
FRA11B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 286.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	110
PHASE1	81
PHASE1/PHASE2	49
Not specified	27
PHASE3	14
PHASE2/PHASE3	2
EARLY_PHASE1	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01339988	PHASE4	UNKNOWN	Busulfan and Cyclophosphamide Instead of Total Boby Irradiation (TBI) and Cyclophosphamide for Hematological Malignancies Hematocrit (HCT)
NCT00843882	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia
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)
NCT04708054	PHASE2/PHASE3	RECRUITING	Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS
NCT05515029	PHASE3	ACTIVE_NOT_RECRUITING	Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis
NCT06647862	PHASE3	RECRUITING	IMM01+Azacitidine VS Placebo +Azacitidine in Patients With Newly Diagnosed Chronic Myelomonocytic Leukemia (CMML1-2)
NCT00002798	PHASE3	COMPLETED	Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
NCT00152139	PHASE3	COMPLETED	Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00186823	PHASE3	COMPLETED	Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00450450	PHASE3	COMPLETED	Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases
NCT00799461	PHASE3	COMPLETED	Internet-Based Program With or Without Telephone-Based Problem-Solving Training in Helping Long-Term Survivors of Hematopoietic Stem Cell Transplant Cope With Late Complications
NCT01241500	PHASE3	COMPLETED	Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts
NCT01305200	PHASE3	COMPLETED	Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant
NCT01749111	PHASE3	TERMINATED	Comparison Between Cyclophosphamide and Combination of Methotrexate + Calcineurin Inhibitor for GVHD Prophylaxis
NCT01928537	PHASE3	COMPLETED	Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine
NCT03306264	PHASE3	COMPLETED	Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML
NCT04842604	PHASE3	COMPLETED	Continuation Study of B1371019(NCT03416179) and B1371012(NCT02367456) Evaluating Azacitidine With Or Without Glasdegib In Patients With Previously Untreated AML, MDS or CMML
NCT00392353	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia
NCT01522976	PHASE2	ACTIVE_NOT_RECRUITING	Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia
NCT01885689	PHASE2	ACTIVE_NOT_RECRUITING	Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
NCT02061800	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Malignant) Stem Cell Selection for Patients Receiving Allogenic Stem Cell Transplant
NCT02727803	PHASE2	RECRUITING	Personalized NK Cell Therapy in CBT
NCT02790515	PHASE2	ACTIVE_NOT_RECRUITING	Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation
NCT02935361	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Guadecitabine and Atezolizumab in Treating Patients With Advanced Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia That Is Refractory or Relapsed
NCT03128034	PHASE1/PHASE2	RECRUITING	211^At-BC8-B10 Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, or Mixed-Phenotype Acute Leukemia
NCT03190915	PHASE2	ACTIVE_NOT_RECRUITING	Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
NCT03289910	PHASE2	ACTIVE_NOT_RECRUITING	Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
NCT03314974	PHASE2	RECRUITING	Myeloablative Allo HSCT With Related or Unrelated Donor for Heme Disorders
NCT03383575	PHASE2	RECRUITING	Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic Syndrome
NCT03418038	PHASE2	RECRUITING	Ascorbic Acid and Chemotherapy for the Treatment of Relapsed or Refractory Lymphoma, CCUS, and Chronic Myelomonocytic Leukemia
NCT03670966	PHASE1/PHASE2	RECRUITING	211At-BC8-B10 Followed by Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory High-Risk Acute Leukemia or Myelodysplastic Syndrome
NCT03672539	PHASE2	ACTIVE_NOT_RECRUITING	Liposome-encapsulated Daunorubicin-Cytarabine and Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome
NCT03683433	PHASE2	RECRUITING	Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation
NCT03722407	PHASE2	ACTIVE_NOT_RECRUITING	Ruxolitinib for the Treatment of Chronic Myelomonocytic Leukemia (CMML): A Phase 2 Expansion
NCT03849651	PHASE2	ACTIVE_NOT_RECRUITING	TCRαβ-depleted Progenitor Cell Graft With Additional Memory T-cell DLI, Plus Selected Use of Blinatumomab, in Naive T-cell Depleted Haploidentical Donor Hematopoietc Cell Transplantation for Hematologic Malignancies
NCT03850574	PHASE1/PHASE2	RECRUITING	Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tuspetinib (HM43239) in Patients With Relapsed or Refractory Acute Myeloid Leukemia
NCT03862157	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
NCT03999723	PHASE2	RECRUITING	Combining Active and Passive DNA Hypomethylation
NCT04093570	PHASE2	ENROLLING_BY_INVITATION	A Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose)
NCT04140487	PHASE1/PHASE2	RECRUITING	Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYCLOPHOSPHAMIDE ANHYDROUS	4	46
CLOFARABINE	4	7
DECITABINE	4	7
AZACITIDINE	4	5
CEDAZURIDINE	4	4
BUSULFAN	4	3
ISOTRETINOIN	4	3
SUNITINIB MALATE	4	3
VENETOCLAX	4	3
CLADRIBINE	4	2
GLASDEGIB	4	2
IDARUBICIN	4	2
IMATINIB	4	2
VEDOLIZUMAB	4	2
ABATACEPT	4	1
ALDESLEUKIN	4	1
ALEMTUZUMAB	4	1
ASPARAGINASE	4	1
CYTARABINE	4	1
DAUNORUBICIN HYDROCHLORIDE	4	1
EPOETIN ALFA	4	1
ETOPOSIDE	4	1
FILGRASTIM	4	1
FLUDARABINE PHOSPHATE	4	1
HYDROCORTISONE	4	1
LENALIDOMIDE	4	1
TEMSIROLIMUS	4	1
THIOGUANINE	4	1
THIOTEPA	4	1
TIPIFARNIB	3	4

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items; also 5 diagnostic, 2 predisposing.

Molecular subtype	Therapy	Effect	Level	CIViC
ZMIZ1::ABL1 Fusion	Azacitidine + Dasatinib	Sensitivity/Response	CIViC C	EID12636