Acute myeloid leukemia with multilineage dysplasia

Summary

Acute myeloid leukemia with multilineage dysplasia (MONDO:0019456) is a cancer with 1 cohort gene (1 CIViC-evidence somatic driver; 1 ClinVar predisposition record) and 6 clinical trials. Top therapeutic interventions include fludarabine phosphate, vosaroxin, and tosedostat.

At a glance

• Classification: Cancer
• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000		Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	acute myeloid leukemia with multilineage dysplasia
Mondo ID	MONDO:0019456
Orphanet	86845
ICD-10-CM	C92.A
ICD-11	1235412948
NCIT	C9289
SNOMED CT	445448008
UMLS	C1292773
MedGen	224861
GARD	0012761
Is cancer (heuristic)	yes

Also known as: acute myeloid leukaemia with myelodysplasia-related features · AML with multilineage dysplasia · AML with myelodysplasia-related features · De novo acute myeloid leukaemia with multilineage dysplasia · De novo acute myeloid leukemia with multilineage dysplasia

Data availability: 1 ClinVar variant.

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 › myeloid leukemia › acute myeloid leukemia › acute myeloid leukemia with multilineage dysplasia

Related subtypes (77): childhood acute myeloid leukemia, acute monocytic leukemia, acute myeloid leukemia with t(8;21)(q22;q22) translocation, acute myeloid leukemia by FAB classification, inherited acute myeloid leukemia, acute myeloid leukemia with CEBPA somatic mutations, acute myeloid leukemia with t(8;16)(p11;p13) translocation, acute myeloid leukemia with t(6;9)(p23;q34), acute myeloid leukemia with t(9;11)(p22;q23), acute myeloid leukemia with inv3(p21;q26.2) or t(3;3)(p21;q26.2), megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13), acute myeloid leukemia with NPM1 somatic mutations, therapy related acute myeloid leukemia and myelodysplastic syndrome, acute leukemia of ambiguous lineage, acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22), acute myeloid leukemia with 11q23 abnormalities, acute myeloid leukemia with BCR-ABL1, acute myeloid leukemia with mutated NPM1, acute myeloid leukemia, inv(16)(p13.1;q22), acute myeloid leukemia, t(16;16)(p13.1;q22), acute myeloid leukemia, t(15;17)(q24;q21), acute myeloid leukemia, t(9;11)(p21.3;q23.3), acute myeloid leukemia, t(10;11)(p12;q23), acute myeloid leukemia, t(10;11)(p11.2;q23), acute myeloid leukemia, t(1;11)(q21;q23), acute myeloid leukemia, t(4;11)(q21;q23), acute myeloid leukemia, t(6;11)(q27;q23), acute myeloid leukemia, t(6;9)(p23;q34.1), acute myeloid leukemia, t(11;19)(q23;p13), acute myeloid leukemia, t(11;19)(q23;p13.1), acute myeloid leukemia, t(11;19)(q23.3;p13.3), acute myeloid leukemia, t(v;11q23.3), acute myeloid leukemia, Monosomy 7, acute myeloid leukemia, Monosomy 5, acute myeloid leukemia, Trisomy 8, acute myeloid leukemia, der12p, acute myeloid leukemia, t(2;12), acute myeloid leukemia, t(11;17), acute myeloid leukemia, t(8;16), acute myeloid leukemia, t(1;22), acute myeloid leukemia, t(5;11)(q35;p15), acute myeloid leukemia, t(7;12)(q36;p13), acute myeloid leukemia, t(9;22)(q34.1;q11.2), acute myeloid leukemia, inv(3)(q21.3;q26.2), acute myeloid leukemia, t(3;3)(q21.3;q26.2), acute myeloid leukemia, t(3;12)(q23;p12.3), acute myeloid leukemia, del(5q31-q32), acute myeloid leukemia, del(13q14-q21), acute myeloid leukemia, loss of chromosome 17p, acute myeloid leukemia, MLL gene rearrangement, acute myeloid leukemia, Non-KMT2A MLLT10 rearrangement positive, acute myeloid leukemia, inv(16)(p13.3;q24.3), acute myeloid leukemia, t(11;15)(p15;q35), acute myeloid leukemia, t(16;21)(q24;q22), acute myeloid leukemia, t(3;5)(q25;q34), acute myeloid leukemia, t(16;21)(p11;q22), acute myeloid leukemia, monoallelic CEBPA gene mutation, acute myeloid leukemia, biallelic CEBPA gene mutation, acute myeloid leukemia, CEBPA gene mutation, acute myeloid leukemia, FLT3 internal tandem duplication, acute myeloid leukemia, FLT3 tyrosine kinase domain point mutation, acute myeloid leukemia, WT1 gene mutation, acute myeloid leukemia, KIT exon 17 mutation, acute myeloid leukemia, KIT exon 8 mutation, acute myeloid leukemia, KIT gene mutation, acute myeloid leukemia, GATA1 gene mutation, acute myeloid leukemia, RUNX1 gene mutation, acute myeloid leukemia, PTPN11 gene mutation, acute myeloid leukemia, NRAS gene mutation, acute myeloid leukemia, KRAS gene mutation, core binding factor acute myeloid leukemia, acute myeloid leukemia, t(8;21)(q22; q22.1), acute myeloid leukemia, t(1;22)(p13;q13), acute myeloid leukemia with CBFA2T3-GLIS2 fusion, acute myeloid leukemia with FUS-ERG fusion, acute myeloid leukemia with MNX1-ETV6 fusion, acute myeloid leukemia with NPM1-MLF1 fusion

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
810668	NM_002520.7(NPM1):c.864_873delinsTTTAAGGATTCGTC (p.Trp288fs)	NPM1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
NPM1	Act	HCC	CIViC #35

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPM1	Orphanet:1775	Dyskeratosis congenita
NPM1	Orphanet:300865	Primary cutaneous anaplastic large cell lymphoma
NPM1	Orphanet:402026	Acute myeloid leukemia with NPM1 somatic mutations
NPM1	Orphanet:520	Acute promyelocytic leukemia
NPM1	Orphanet:98833	Acute myeloblastic leukemia without maturation
NPM1	Orphanet:98834	Acute myeloblastic leukemia with maturation
NPM1	Orphanet:98842	Lymphomatoid papulosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPM1	HGNC:7910	ENSG00000181163	P06748	Nucleophosmin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPM1	Nucleophosmin	Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPM1	Other/Unknown	no		Nucleoplasmin, Nucleoplasmin_core_dom, NPM1_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
left ovary	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPM1	276	ubiquitous	marker	calcaneal tendon, left ovary, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPM1	7,589

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPM1	P06748	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	2284.0×	0.004	NPM1
ALK mutants bind TKIs	1	951.7×	0.005	NPM1
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	519.1×	0.006	NPM1
Nuclear import of Rev protein	1	335.9×	0.006	NPM1
Nuclear events stimulated by ALK signaling in cancer	1	326.3×	0.006	NPM1
SUMOylation of transcription cofactors	1	243.0×	0.007	NPM1
SARS-CoV-1-host interactions	1	175.7×	0.007	NPM1
Deposition of new CENPA-containing nucleosomes at the centromere	1	158.6×	0.007	NPM1
Signaling by ALK fusions and activated point mutants	1	150.3×	0.007	NPM1
PKR-mediated signaling	1	141.0×	0.007	NPM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of eIF2 alpha phosphorylation by dsRNA	1	16852.0×	0.001	NPM1
regulation of mRNA stability involved in cellular response to UV	1	16852.0×	0.001	NPM1
positive regulation of cell cycle G2/M phase transition	1	5617.3×	0.002	NPM1
positive regulation of centrosome duplication	1	3370.4×	0.002	NPM1
negative regulation of centrosome duplication	1	3370.4×	0.002	NPM1
negative regulation of protein kinase activity by regulation of protein phosphorylation	1	3370.4×	0.002	NPM1
positive regulation of protein localization to nucleolus	1	2808.7×	0.002	NPM1
ribosomal large subunit export from nucleus	1	2407.4×	0.002	NPM1
ribosomal small subunit export from nucleus	1	2106.5×	0.002	NPM1
regulation of DNA damage response, signal transduction by p53 class mediator	1	2106.5×	0.002	NPM1
ribosome assembly	1	1872.4×	0.002	NPM1
regulation of centriole replication	1	1685.2×	0.002	NPM1
negative regulation of mRNA splicing, via spliceosome	1	766.0×	0.004	NPM1
regulation of centrosome duplication	1	732.7×	0.004	NPM1
cell volume homeostasis	1	601.9×	0.004	NPM1
macrophage differentiation	1	468.1×	0.005	NPM1
ribosomal large subunit biogenesis	1	443.5×	0.005	NPM1
nucleocytoplasmic transport	1	391.9×	0.006	NPM1
centrosome cycle	1	337.0×	0.006	NPM1
cellular response to UV	1	295.6×	0.006	NPM1
cellular senescence	1	295.6×	0.006	NPM1
ribosomal small subunit biogenesis	1	227.7×	0.007	NPM1
positive regulation of translation	1	227.7×	0.007	NPM1
regulation of cell growth	1	221.7×	0.007	NPM1
positive regulation of protein ubiquitination	1	213.3×	0.007	NPM1
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.007	NPM1
protein import into nucleus	1	144.0×	0.010	NPM1
nucleosome assembly	1	140.4×	0.010	NPM1
intracellular protein localization	1	104.7×	0.013	NPM1
chromatin remodeling	1	73.0×	0.018	NPM1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
NPM1	CERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPM1	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERITINIB	4	NPM1
BOSUTINIB	4	NPM1
CRIZOTINIB	4	NPM1
MOLIBRESIB	2	NPM1
ASP-3026	1	NPM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NPM1	113	Binding:108, Functional:5

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NPM1	113

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

5 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)
CERITINIB	4	NPM1
BOSUTINIB	4	NPM1
CRIZOTINIB	4	NPM1
MOLIBRESIB	2	NPM1
ASP-3026	1	NPM1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NPM1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	4
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04802161	PHASE2	ACTIVE_NOT_RECRUITING	Comparing the Addition of an Anti-Cancer Drug, Pomalidomide, to the Usual Chemotherapy Treatment (Daunorubicin and Cytarabine Liposome) in Newly Diagnosed Acute Myeloid Leukemia With Myelodysplastic Syndrome-Related Changes
NCT01028716	PHASE2	TERMINATED	Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01567059	PHASE2	COMPLETED	Tosedostat in Combination With Cytarabine or Decitabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
NCT02658487	PHASE2	COMPLETED	Vosaroxin and Infusional Cytarabine in Treating Patients With Untreated Acute Myeloid Leukemia
NCT03047993	PHASE1/PHASE2	COMPLETED	Glutaminase Inhibitor CB-839 and Azacitidine in Treating Patients With Advanced Myelodysplastic Syndrome
NCT04869683	Not specified	RECRUITING	Biocollection in MyeloDysplastic Syndrome (P-MDS)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	1
VOSAROXIN	3	1
TOSEDOSTAT	2	1
CHEMBL4206158	0	1
CHEMBL4591371	0	1