Childhood acute lymphoblastic leukemia

Summary

Childhood acute lymphoblastic leukemia (MONDO:0000870) is a cancer with 2 cohort genes (1 GWAS associations across 4 studies; 1 CIViC-evidence somatic driver) and 356 clinical trials. Molecularly, NUDT15 Inactivating Mutation confers sensitivity to Azathioprine + Mercaptopurine + Thioguanine in Childhood Acute Lymphocytic Leukemia (CIViC Level B); 7 further subtype–drug associations are mapped below. Top therapeutic interventions include etoposide, 2-mercaptoethanesulfonic acid, and dexrazoxane.

At a glance

• Classification: Cancer
• Cohort genes: 2
• GWAS associations: 1
• Clinical trials: 356
• Precision-medicine evidence (CIViC): 8 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	childhood acute lymphoblastic leukemia
Mondo ID	MONDO:0000870
DOID	DOID:0080144
NCIT	C3168
UMLS	C0023452
MedGen	44122
GARD	0009240
Is cancer (heuristic)	yes

Also known as: acute lymphoblastic leukaemia (ALL) · acute lymphoblastic leukemia (ALL) · childhood acute lymphoblastic leukemia · childhood acute lymphocytic leukaemia · childhood acute lymphocytic leukemia · childhood acute lymphogenous leukaemia · childhood acute lymphogenous leukemia · childhood acute lymphoid leukaemia · childhood acute lymphoid leukemia · childhood ALL · childhood precursor lymphoblastic leukaemia · childhood precursor lymphoblastic leukemia · paediatric acute lymphoblastic leukaemia · paediatric acute lymphocytic leukaemia · paediatric acute lymphocytic leukaemia (ALL) · paediatric acute lymphogenous leukaemia · paediatric acute lymphoid leukaemia · paediatric ALL · pediatric acute lymphoblastic leukemia · pediatric acute lymphocytic leukemia (+4 more)

Data availability: 1 GWAS association (4 studies) · 13 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

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 › lymphoid neoplasm › lymphoma › pediatric lymphoma › childhood acute lymphoblastic leukemia

Related subtypes (2): T-cell childhood lymphoblastic lymphoma, systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood

Subtypes (2): T-cell childhood acute lymphocytic leukemia, B-cell childhood acute lymphoblastic leukemia

Genetics & variants

GWAS landscape

1 GWAS associations across 4 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7090445	3e-14	ARID5B	?	1.96

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90320046	Jeon S	2023	2,306	59,072	Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.
GCST90320047	Jeon S	2023	2,306	59,072	Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.
GCST90320048	Jeon S	2023	1,518	7,210	Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.
GCST012360	Hao Q	2021	381	1,466	Age-related differences of genetic susceptibility to patients with acute lymphoblastic leukemia.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

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

MAF distribution

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

Functional consequences

Consequence	Count
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7090445	10	61961417	C>G,T	0.05	intron_variant	ARID5B	3e-14	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
NT5C2			CIViC #9189

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NT5C2	Orphanet:320396	Autosomal recessive spastic paraplegia type 45

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	1
civic_only	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NT5C2	HGNC:8022	ENSG00000076685	P49902	Cytosolic purine 5’-nucleotidase	civic_evidence
ARID5B	HGNC:17362	ENSG00000150347	Q14865	AT-rich interactive domain-containing protein 5B	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NT5C2	Cytosolic purine 5’-nucleotidase	Broad specificity cytosolic 5’-nucleotidase that catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5’-monophosphates.
ARID5B	AT-rich interactive domain-containing protein 5B	Transcription coactivator that binds to the 5’-AATA[CT]-3’ core sequence and plays a key role in adipogenesis and liver development.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NT5C2	Enzyme (other)	yes	3.1.3.5	HAD-SF_hydro_IG_5-nucl, Pur_nucleotidase, HAD_sf
ARID5B	Other/Unknown	no		ARID_dom, ARID5B_ARID/BRIGHT_DNA-bd, ARID_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
oral cavity	1
parotid gland	1
pericardium	1
saphenous vein	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NT5C2	294	ubiquitous	marker	parotid gland, buccal mucosa cell, oral cavity
ARID5B	299	ubiquitous	marker	type B pancreatic cell, saphenous vein, pericardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARID5B	1,778
NT5C2	1,513

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NT5C2	P49902	43
ARID5B	Q14865	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Abacavir metabolism	1	1427.5×	0.004	NT5C2
Abacavir ADME	1	713.8×	0.004	NT5C2
Nucleotide catabolism	1	634.4×	0.004	NT5C2
Purine catabolism	1	519.1×	0.004	NT5C2
Ribavirin ADME	1	519.1×	0.004	NT5C2
Metabolism of nucleotides	1	150.3×	0.012	NT5C2
HDMs demethylate histones	1	114.2×	0.012	ARID5B
Drug ADME	1	114.2×	0.012	NT5C2
Chromatin organization	1	40.8×	0.030	ARID5B
Chromatin modifying enzymes	1	36.1×	0.030	ARID5B
Metabolism	1	5.8×	0.165	NT5C2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete GMP catabolic process to guanine	1	8426.0×	0.003	NT5C2
GMP metabolic process	1	2808.7×	0.003	NT5C2
dGMP metabolic process	1	2808.7×	0.003	NT5C2
IMP metabolic process	1	2106.5×	0.003	NT5C2
negative regulation of defense response to virus by host	1	2106.5×	0.003	NT5C2
IMP catabolic process	1	1685.2×	0.003	NT5C2
dGMP catabolic process	1	1404.3×	0.003	NT5C2
adenosine metabolic process	1	1203.7×	0.003	NT5C2
obsolete amide catabolic process	1	1053.2×	0.003	NT5C2
allantoin metabolic process	1	936.2×	0.003	NT5C2
muscle organ morphogenesis	1	936.2×	0.003	ARID5B
fat pad development	1	842.6×	0.003	ARID5B
cell development	1	443.5×	0.005	ARID5B
fibroblast migration	1	421.3×	0.005	ARID5B
female gonad development	1	401.2×	0.005	ARID5B
adrenal gland development	1	337.0×	0.006	ARID5B
obsolete positive regulation of DNA-binding transcription factor activity	1	300.9×	0.006	ARID5B
platelet-derived growth factor receptor signaling pathway	1	280.9×	0.007	ARID5B
skeletal system morphogenesis	1	247.8×	0.007	ARID5B
face morphogenesis	1	247.8×	0.007	ARID5B
adipose tissue development	1	200.6×	0.008	ARID5B
roof of mouth development	1	123.9×	0.012	ARID5B
liver development	1	110.9×	0.013	ARID5B
post-embryonic development	1	102.8×	0.013	ARID5B
fat cell differentiation	1	90.6×	0.015	ARID5B
protein K48-linked ubiquitination	1	84.3×	0.015	NT5C2
cellular response to leukemia inhibitory factor	1	79.5×	0.015	ARID5B
male gonad development	1	78.0×	0.015	ARID5B
kidney development	1	70.2×	0.016	ARID5B
multicellular organism growth	1	68.5×	0.016	ARID5B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NT5C2	0	0
ARID5B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NT5C2	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NT5C2	3.1.3.5	5’-nucleotidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	NT5C2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARID5B

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)
NT5C2	7	—
ARID5B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 356.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	231
PHASE2	45
PHASE1	35
PHASE1/PHASE2	17
PHASE4	13
PHASE3	11
PHASE2/PHASE3	2
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05682131	PHASE4	RECRUITING	South China Children Cancer Group - Relapsed-Acute Lymphoblastic Leukemia 2022 Protocol
NCT06035757	PHASE4	RECRUITING	The Occurrence of Emergence Agitation in Pediatric Strabismus Surgery
NCT06410833	PHASE4	RECRUITING	Belimumab After Rituximab in Resistant Primary Juvenile SS
NCT06711679	PHASE4	ENROLLING_BY_INVITATION	Exploring the Minimum Effective Concentration and Volume of Ropivacaine for Sacral Plexus Anesthesia
NCT01735955	PHASE4	COMPLETED	Study to Allow Access to Nilotinib for Patients Who Are on Nilotinib Treatment in a Novartis-sponsored Study
NCT01990807	PHASE4	UNKNOWN	Treatment Protocol of Children With Philadelphia Chromosome Negative High Risk Acute Lymphoblastic Leukemia
NCT02894645	PHASE4	UNKNOWN	Malaysia-Singapore Acute Lymphoblastic Leukemia 2010 Study
NCT03043430	PHASE4	TERMINATED	Intranasal Ketamine for Anxiolysis in Pediatric Emergency Department Patients
NCT03176849	PHASE4	COMPLETED	A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 in Pediatric Patients Undergoing HSCT
NCT03318393	PHASE4	COMPLETED	Study Comparing Bivalirudin Versus Heparin in Neonatal and Pediatric ECMO
NCT03369847	PHASE4	COMPLETED	Inhaled Steroids for Pediatric Asthma at Pediatric Emergency Medicine Discharge
NCT04846855	PHASE4	COMPLETED	Regional Anesthesia for Totally Awake Upper Limb Surgery in PEDiatric Population
NCT05176119	PHASE4	COMPLETED	Nalbuphine Versus Ketamine for Prevention of Emergence Agitation After Sevoflurane in Children Undergoing Tonsillectomy
NCT04851717	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Investigation of Remimazolam in Children Undergoing Sedation for Medical Procedures
NCT07297914	PHASE2/PHASE3	NOT_YET_RECRUITING	Framework for Optimizing, Refining, and Unifying Management of HSCT in Pediatric ALL
NCT00022737	PHASE3	COMPLETED	Combination Chemotherapy With or Without Peripheral Stem Cell Transplant in Treating Children With Acute Lymphoblastic Leukemia
NCT00450450	PHASE3	COMPLETED	Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases
NCT01305200	PHASE3	COMPLETED	Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant
NCT01305655	PHASE3	COMPLETED	Glucarpidase Effect on Severe Delayed HDM-clearance in Children Treated With High-dose Mtx in ALL
NCT01371656	PHASE3	COMPLETED	Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation
NCT01439347	PHASE3	TERMINATED	A Phase 3 Study to Evaluate Marqibo® in the Treatment of Subjects ≥ 60 Years Old With Newly Diagnosed ALL
NCT01802814	PHASE3	COMPLETED	International Study for Treatment of Standard Risk Childhood Relapsed ALL 2010
NCT01817075	PHASE3	COMPLETED	Chlorhexidine Gluconate Cleansing in Preventing Central Line Associated Bloodstream Infection and Acquisition of Multi-drug Resistant Organisms in Younger Patients With Cancer or Undergoing Donor Stem Cell Transplant
NCT02730299	PHASE3	COMPLETED	Stem Cell Transplantation With NiCord® (Omidubicel) vs Standard UCB in Patients With Leukemia, Lymphoma, and MDS
NCT05233683	PHASE3	UNKNOWN	Caudal Block Versus Dorsal Penile Nerve Block Plus Ring Block for Pain Management of Different Surgical Techniques of Circumcision in Infants and Children
NCT06179732	PHASE3	COMPLETED	Field Evaluations of Innovative Tools for Vector-borne Disease Control in Conflict-affected Communities
NCT02061800	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Malignant) Stem Cell Selection for Patients Receiving Allogenic Stem Cell Transplant
NCT02094794	PHASE2	ACTIVE_NOT_RECRUITING	Total Marrow and Lymphoid Irradiation and Chemotherapy Before DSCT in Treating Patients With High-Risk ALL or AML
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
NCT03590171	PHASE2	RECRUITING	International Study for Treatment of High Risk Childhood Relapsed ALL 2010
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
NCT05884333	PHASE2	RECRUITING	Cord Blood Transplant in Adults With Blood Cancers
NCT06184009	PHASE2	RECRUITING	Treatment of Newly Diagnosed High Risk Pediatric Acute Lymphoblastic Leukemia
NCT07227584	PHASE2	NOT_YET_RECRUITING	ALL Backbone in AYAs
NCT00002970	PHASE2	COMPLETED	506U78 in Treating Patients With Refractory Hematologic Cancer
NCT00005811	PHASE2	COMPLETED	Topotecan Hydrochloride in Treating Children With Meningeal Cancer That Has Not Responded to Previous Treatment
NCT00006251	PHASE1/PHASE2	COMPLETED	Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine, Mycophenolate Mofetil, Donor Lymphocyte Infusion in Treating Patients With Hematopoietic Cancer
NCT00027820	PHASE1/PHASE2	COMPLETED	Total-Body Irradiation and Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer
NCT00031655	PHASE2	COMPLETED	Reduced Intensity Donor Stem Cell Transplant in Treating Patients With High Risk Acute Lymphocytic Leukemia in Complete Remission
NCT00036738	PHASE2	COMPLETED	Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ETOPOSIDE	4	8
2-MERCAPTOETHANESULFONIC ACID	4	6
DEXRAZOXANE	4	6
ASPARAGINASE	4	4
DAUNORUBICIN	4	4
IMATINIB	4	4
MERCAPTOPURINE ANHYDROUS	4	4
NILOTINIB	4	4
PEGASPARGASE	4	4
ALEMTUZUMAB	4	3
BLINATUMOMAB	4	3
CYCLOPHOSPHAMIDE ANHYDROUS	4	3
DOXORUBICIN	4	3
LEUCOVORIN	4	3
VINCRISTINE	4	3
CYTARABINE	4	2
DASATINIB ANHYDROUS	4	2
PYRIDOSTIGMINE	4	2
REVUMENIB	4	2
THIOGUANINE	4	2
ATORVASTATIN CALCIUM	4	1
AXICABTAGENE CILOLEUCEL	4	1
BECLOMETHASONE DIPROPIONATE	4	1
BELIMUMAB	4	1
BIVALIRUDIN	4	1
BUDESONIDE	4	1
DIPHENHYDRAMINE HYDROCHLORIDE	4	1
ETOPOSIDE PHOSPHATE	4	1
FILGRASTIM	4	1
FLUDARABINE PHOSPHATE	4	1

Precision-medicine subtype map (CIViC)

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

Molecular subtype	Therapy	Effect	Level	CIViC
NUDT15 Inactivating Mutation	Azathioprine + Mercaptopurine + Thioguanine	Adverse Response	CIViC B	EID7794
NT5C2 R367Q	Mercaptopurine + Thioguanine	Resistance	CIViC C	EID7812
NT5C2 R238W	Mercaptopurine + Thioguanine	Resistance	CIViC D	EID7813
NT5C2 R238W	Cytarabine + Gemcitabine + Doxorubicin + Prednisolone	Resistance	CIViC D	EID7816
NT5C2 R367Q	Cytarabine + Gemcitabine + Prednisolone + Doxorubicin	Resistance	CIViC D	EID7815
NT5C2 R367Q	Thioguanine + Mercaptopurine	Resistance	CIViC D	EID7862
NT5C2 S445F	Mercaptopurine + Thioguanine	Resistance	CIViC D	EID7814
NT5C2 S445F	Cytarabine + Doxorubicin + Gemcitabine + Prednisolone	Resistance	CIViC D	EID7817