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Atlas / Disease / Acute megakaryoblastic leukemia without down syndrome

Acute megakaryoblastic leukemia without down syndrome

disease
On this page

Also known as non-DS-AMKL

Summary

Acute megakaryoblastic leukemia without down syndrome (MONDO:0018004) is a cancer with 5 cohort genes (4 CIViC-evidence somatic drivers; 7 ClinVar predisposition records). The dominant Reactome pathway is Chromatin organization (3 cohort genes).

At a glance

  • Classification: Cancer
  • Prevalence: Unknown (Worldwide)
  • Cohort genes: 5
  • ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical nameacute megakaryoblastic leukemia without down syndrome
Mondo IDMONDO:0018004
Orphanet329469
UMLSC5679860
MedGen1843134
GARD0021490
Is cancer (heuristic)yes

Also known as: non-DS-AMKL

Data availability: 7 ClinVar variants.

Disease family

Classification path: 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 by FAB classification › acute megakaryoblastic leukemia › acute megakaryoblastic leukemia without down syndrome

Related subtypes (4): acute megakaryoblastic leukemia in down syndrome, childhood acute megakaryoblastic leukemia, myeloid leukemia associated with down syndrome, acute megakaryoblastic leukemia in adult

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

7 retrieved; paginated sample, class counts are floors:

4 pathogenic, 3 likely pathogenic

ClinVarVariant (HGVS)GeneClassificationReview
998057inv(16)(p13.3q24.3)CBFA2T3Pathogeniccriteria provided, single submitter
998058t(16;16)(p13.3;q24.3)CBFA2T3Pathogeniccriteria provided, single submitter
998056t(11;12)(p15;p13)KDM5APathogeniccriteria provided, single submitter
998059t(11;17)(q23;q12-q21)KMT2APathogeniccriteria provided, single submitter
268131NM_000121.4(EPOR):c.1316G>A (p.Trp439Ter)EPORLikely pathogeniccriteria provided, single submitter
998060NM_014159.7(SETD2):c.3918G>A (p.Trp1306Ter)SETD2Likely pathogeniccriteria provided, single submitter
998061NM_014159.7(SETD2):c.1321C>T (p.Arg441Ter)SETD2Likely pathogeniccriteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

GeneintOGen roleCancer typesCIViC
SETD2LoFALL,CCRCC,CLLSLL,EGC,ES,GB,GIST,HCC,LGGNOS,LUAD,MEL,NSCLC,OS,PAAD,PANCREAS,PANET,PAST,PCM,PLMESO,PRAD,PRCC,RCC,SKCMCIViC #11289
EPORCIViC #1728
KMT2ALoFACC,BLCA,ESCC,HCC,OVT,PAAD,PRAD,SIC,WDTCCIViC #3537
KDM5AActGBC

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
CBFA2T3Orphanet:329469Acute megakaryoblastic leukemia in children without Down syndrome
SETD2Orphanet:597738Luscan-Lumish syndrome
SETD2Orphanet:597743SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
EPOROrphanet:90042Primary familial polycythemia
KMT2AOrphanet:319182Wiedemann-Steiner syndrome
KMT2AOrphanet:402017Acute myeloid leukemia with t(9;11)(p22;q23)
KMT2AOrphanet:585918B-lymphoblastic leukemia/lymphoma with t(v;11q23.3)
KMT2AOrphanet:589534Mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2)
KMT2AOrphanet:589595Mixed phenotype acute leukemia with t(v;11q23.3)
KMT2AOrphanet:98831Acute myeloid leukemia with 11q23 abnormalities
KMT2AOrphanet:98835Acute undifferentiated leukemia

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence5

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
CBFA2T3HGNC:1537ENSG00000129993O75081Transcriptional corepressor CBFA2T3clinvar
SETD2HGNC:18420ENSG00000181555Q9BYW2Histone-lysine N-methyltransferase SETD2clinvar
EPORHGNC:3416ENSG00000187266P19235Erythropoietin receptorclinvar
KMT2AHGNC:7132ENSG00000118058Q03164Histone-lysine N-methyltransferase 2Aclinvar
KDM5AHGNC:9886ENSG00000073614P29375Lysine-specific demethylase 5Aclinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
CBFA2T3Transcriptional corepressor CBFA2T3Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes.
SETD2Histone-lysine N-methyltransferase SETD2Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate.
EPORErythropoietin receptorReceptor for erythropoietin, which mediates erythropoietin-induced erythroblast proliferation and differentiation.
KMT2AHistone-lysine N-methyltransferase 2AHistone methyltransferase that plays an essential role in early development and hematopoiesis.
KDM5ALysine-specific demethylase 5AHistone demethylase that specifically demethylates ‘Lys-4’ of histone H3, thereby playing a central role in histone code.

Protein-family classification

Druggable: 1 · Difficult: 4 · Unknown: 0 · 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.

FamilyGenesFoldFDR
Transcription factor35.0×0.044
Antibody/Immunoglobulin15.8×0.240
Scaffold/PPI13.5×0.258

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
CBFA2T3Transcription factornoZnf_MYND, TAFH_NHR1, CBFA2T1/2/3
SETD2Scaffold/PPIno2.1.1.359WW_dom, SET_dom, Post-SET_dom
EPORAntibody/ImmunoglobulinyesLong_hematopoietin_rcpt_CS, FN3_dom, Erythropoietin_rcpt
KMT2ATranscription factornoSET_dom, Bromodomain, Znf_PHD
KDM5ATranscription factorno1.14.11.67ARID_dom, Znf_PHD, JmjC_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)5
unknown0

Top tissues across cohort

TissueCohort genes
colonic epithelium3
cerebellar hemisphere1
endometrium epithelium1
right hemisphere of cerebellum1
endothelial cell1
tendon of biceps brachii1
left lobe of thyroid gland1
olfactory bulb1
type B pancreatic cell1
sural nerve1
ventricular zone1
caput epididymis1
cranial nerve II1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
CBFA2T3197broadmarkerendometrium epithelium, right hemisphere of cerebellum, cerebellar hemisphere
SETD2291ubiquitousmarkertendon of biceps brachii, endothelial cell, colonic epithelium
EPOR268ubiquitousmarkertype B pancreatic cell, olfactory bulb, left lobe of thyroid gland
KMT2A285ubiquitousmarkerventricular zone, colonic epithelium, sural nerve
KDM5A287ubiquitousmarkercolonic epithelium, caput epididymis, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
SETD24,668
KMT2A4,314
KDM5A4,006
CBFA2T32,092
EPOR1,563

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
KMT2AQ0316460
KDM5AP2937546
SETD2Q9BYW243
EPORP1923522
CBFA2T3O750811

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Chromatin organization361.2×1e-04SETD2, KMT2A, KDM5A
Chromatin modifying enzymes354.2×1e-04SETD2, KMT2A, KDM5A
PKMTs methylate histone lysines280.4×0.002SETD2, KMT2A
Erythropoietin activates Phospholipase C gamma (PLCG)1407.9×0.013EPOR
Erythropoietin activates STAT51407.9×0.013EPOR
Signaling by Erythropoietin1259.6×0.014EPOR
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)1237.9×0.014EPOR
Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters1219.6×0.014KMT2A
Erythropoietin activates RAS1190.3×0.014EPOR
Maternal to zygotic transition (MZT)1178.4×0.014KDM5A
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex1178.4×0.014KMT2A
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes1119.0×0.019KMT2A
Formation of WDR5-containing histone-modifying complexes166.4×0.031KMT2A
HDMs demethylate histones157.1×0.034KDM5A
Chromatin modifications during the maternal to zygotic transition (MZT)140.8×0.038KDM5A
Epigenetic regulation by WDR5-containing histone modifying complexes138.6×0.038KMT2A
Transcriptional regulation by RUNX1136.6×0.038KMT2A
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)136.6×0.038KMT2A
Developmental Biology27.2×0.038KMT2A, KDM5A
Transcriptional regulation of granulopoiesis131.4×0.042KMT2A
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function130.1×0.042KMT2A
Regulation of PD-L1(CD274) transcription127.2×0.045KMT2A
RUNX1 regulates transcription of genes involved in differentiation of HSCs123.8×0.049KMT2A
Epigenetic regulation of gene expression117.8×0.062KMT2A
RNA Polymerase II Transcription15.6×0.179KMT2A
Gene expression (Transcription)14.5×0.214KMT2A
Generic Transcription Pathway13.8×0.240KMT2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
transcription initiation-coupled chromatin remodeling2153.2×0.004KMT2A, KDM5A
circadian regulation of gene expression293.6×0.005KMT2A, KDM5A
negative regulation of DNA methylation-dependent heterochromatin formation11685.2×0.011KMT2A
regulation of protein localization to chromatin11123.5×0.011SETD2
microtubule cytoskeleton organization involved in mitosis1842.6×0.011SETD2
peptidyl-lysine trimethylation1561.7×0.011SETD2
nucleosome organization1561.7×0.011SETD2
erythropoietin-mediated signaling pathway1561.7×0.011EPOR
regulation of mRNA export from nucleus1421.3×0.011SETD2
response to potassium ion1421.3×0.011KMT2A
facultative heterochromatin formation1421.3×0.011KDM5A
regulation of aerobic respiration1421.3×0.011CBFA2T3
response to type I interferon1374.5×0.011SETD2
T-helper 2 cell differentiation1374.5×0.011KMT2A
response to metal ion1306.4×0.012SETD2
response to alkaloid1306.4×0.012SETD2
granulocyte differentiation1240.7×0.014CBFA2T3
regulation of short-term neuronal synaptic plasticity1224.7×0.014KMT2A
negative regulation of glycolytic process1210.7×0.014CBFA2T3
regulation of double-strand break repair via homologous recombination1198.3×0.014SETD2
embryonic hemopoiesis1198.3×0.014KMT2A
positive regulation of ossification1187.2×0.014SETD2
definitive hemopoiesis1187.2×0.014KMT2A
decidualization1134.8×0.017EPOR
mismatch repair1129.6×0.017SETD2
positive regulation of interferon-alpha production1129.6×0.017SETD2
exploration behavior1129.6×0.017KMT2A
membrane depolarization1102.1×0.019KMT2A
endodermal cell differentiation199.1×0.019SETD2
negative regulation of fibroblast proliferation199.1×0.019KMT2A

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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.

SymbolExample approved molecule
KMT2AFLUORESCEIN
KDM5ADEFERASIROX

Top cohort targets by molecule count

SymbolMoleculesMax phase
KMT2A5354
KDM5A64
SETD232
CBFA2T300
EPOR00

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
FLUORESCEIN4KMT2A
METHYSERGIDE4KMT2A
OXCARBAZEPINE4KMT2A
TRYPAN BLUE FREE ACID4KMT2A
RALOXIFENE HYDROCHLORIDE4KMT2A
IDARUBICIN4KMT2A
DULOXETINE4KMT2A
PYRITHIONE ZINC4KMT2A
HYDROCORTISONE VALERATE4KMT2A
PROMETHAZINE HYDROCHLORIDE4KMT2A
THIORIDAZINE HYDROCHLORIDE4KMT2A
METHYSERGIDE MALEATE4KMT2A
THIOTHIXENE4KMT2A
METHANTHELINE4KMT2A
ROSE BENGAL FREE ACID4KMT2A
BENZYL BENZOATE4KMT2A
NOMIFENSINE MALEATE4KMT2A
ANTAZOLINE4KMT2A
CARBOPLATIN4KMT2A
FLUVOXAMINE MALEATE4KMT2A
MITOXANTRONE HYDROCHLORIDE4KMT2A
ESTRADIOL VALERATE4KMT2A
EPHEDRINE SULFATE4KMT2A
DACTINOMYCIN4KMT2A
DAUNORUBICIN HYDROCHLORIDE4KMT2A
TOPOTECAN HYDROCHLORIDE4KMT2A
PHENYTOIN SODIUM4KMT2A
TAZAROTENE4KMT2A
DILTIAZEM HYDROCHLORIDE4KMT2A
SERTRALINE HYDROCHLORIDE4KMT2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

SymbolAssaysType breakdown
KMT2A188Binding:180, Functional:8
KDM5A165Binding:165
SETD264Binding:64
EPOR9Binding:9

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
SETD22.1.1.359[histone H3]-lysine36 N-trimethyltransferase
KDM5A1.14.11.67[histone H3]-trimethyl-L-lysine4 demethylase

Cohort genes with high screening signal

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

SymbolChEMBL assays
KMT2A188
KDM5A165

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

30 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.

CompoundMax phaseCohort target (bioactivity)
FLUORESCEIN4KMT2A
METHYSERGIDE4KMT2A
OXCARBAZEPINE4KMT2A
TRYPAN BLUE FREE ACID4KMT2A
RALOXIFENE HYDROCHLORIDE4KMT2A
IDARUBICIN4KMT2A
DULOXETINE4KMT2A
PYRITHIONE ZINC4KMT2A
HYDROCORTISONE VALERATE4KMT2A
PROMETHAZINE HYDROCHLORIDE4KMT2A
THIORIDAZINE HYDROCHLORIDE4KMT2A
METHYSERGIDE MALEATE4KMT2A
THIOTHIXENE4KMT2A
METHANTHELINE4KMT2A
ROSE BENGAL FREE ACID4KMT2A
BENZYL BENZOATE4KMT2A
NOMIFENSINE MALEATE4KMT2A
ANTAZOLINE4KMT2A
CARBOPLATIN4KMT2A
FLUVOXAMINE MALEATE4KMT2A
MITOXANTRONE HYDROCHLORIDE4KMT2A
ESTRADIOL VALERATE4KMT2A
EPHEDRINE SULFATE4KMT2A
DACTINOMYCIN4KMT2A
DAUNORUBICIN HYDROCHLORIDE4KMT2A
TOPOTECAN HYDROCHLORIDE4KMT2A
PHENYTOIN SODIUM4KMT2A
TAZAROTENE4KMT2A
DILTIAZEM HYDROCHLORIDE4KMT2A
SERTRALINE HYDROCHLORIDE4KMT2A

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)2KMT2A, KDM5A
BPhased (≥1) drug, not yet approved1SETD2
CDruggable family + PDB, no drug1EPOR
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug1CBFA2T3

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
CBFA2T30—
EPOR9—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
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This page pulls from 70 datasets indexed by BioBTree:

alphafoldantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetciviccivic_evidenceclingen_dosageclinical_trialsclinvarctd_gene_interactiondepmapdiamond_similarityefoensemblentrezesm2_similarityfantom5_genefantom5_promotergardgenccgenerifgogtopdbgtopdb_interactiongwasgwas_studyhgncintactinterprointogenmedgenmeshmimmondomondochildmondoparentorphanetpatentpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assayreactomerefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorstring_interactiontranscriptufeatureumlsuniprot