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Pediatric acute lymphoblastic leukemia
Table 2. Genetic alterations, age distribution, clinical features, and genetic-based therapy in pediatric B- and T-acute lymphoblastic leukemia.
Category Age
B-cell precursor acute lymphoblastic leukemia
Description
Excellent prognosis; mutations in Ras signaling pathway
and histone modifiers
24-31 chromosomes; poor prognosis; Ras-activating
mutations; inactivation of IKZF3
32-39 chromosomes; poor prognosis; TP53 mutations
(somatic and germline)
Complex alterations of chromosome 21; requires
high-risk therapy for good outcomes
Excellent prognosis; cryptic rearrangement that is detectable by FISH
Absence of ETV6-RUNX1 fusion; mutations in both ETV6 and IKZF1
Increased incidence in African Americans; favorable prognosis
Historically poor prognosis, improved with tyrosine kinase
inhibitors; common deletions of IKZF1
Kinase-activating lesions; poor outcome; potentially amenable to kinase inhibition
Common in Down syndrome and Ph-like ALL; associated with IKZF1 deletion and JAK1/2 mutation
Common in infant ALL; dismal prognosis; few co-operating mutations, commonly in RAS signaling pathway
Distinct gene expression profile; most have focal ERG
deletions and favorable outcome despite IKZF1 alterations Distinct gene expression profile; potential sensitivity
to HDAC inhibition
Pro-B ALL phenotype; expression of myeloid markers;
increased expression of FLT3
PAX5 fusions, mutation, or amplifications;
intermediate prognosis
Frequent signaling pathway alterations
Rare; unknown prognosis
Exclusively in children; rare; excellent prognosis Rare; dismal prognosis
Poor prognosis
Enrichment of mutation in PI3K signaling pathway
Poor prognosis; frequent co-operating mutation
in ubiquitination and ribosomal genes
Frequent mutations in JAK-STAT pathway, KMT2A rearrangements
Favorable prognosis
Poor prognosis; enriched for ETP-ALL, frequent co-operating mutation in JAK-/STAT
Frequent co-operating mutation in ribosomal genes
Neutral prognosis, in contrast to kinase driven B-ALL; potentially amenable to tyrosine kinase inhibition
Poor prognosis; genetically heterogeneous with mutations in hematopoietic regulators, cytokine and Ras signaling, and epigenetic modifiers
Potential therapeutic implications
Reduction of intensity
BCL2 inhibitors
BCL2 inhibitors
Intensification of therapy
Reduction of intensity
Reduction of intensity
ABL1 inhibitors, FAK inhibitors, rexinoids,
BCL2 inhibitors
ABL1 inhibitors, JAK inhibitors, PI3K inhibitors, BCL2 inhibitors
JAK inhibitors, BCL2 inhibitors
DOT1L inhibitors, menin inhibitors, proteasome inhibitors, HDAC inhibitors, BCL2 inhibitors
Reduction of intensity
HDAC inhibitors
FLT3 inhibitors
Kinase inhibitors
FAK inhibitors, rexinoids
HDAC inhibitors, bromodomain inhibitors BCL2 inhibitors
PI3K inhibitors, nelarabine, BCL2 inhibitors
Nelarabine, BCL2 inhibitors
JAK inhibitors, nelarabine, BCL2 inhibitors
Nelarabine, BCL2 inhibitors
JAK inhibitors, nelarabine, BCL2 inhibitors
Nelarabine, BCL2 inhibitors
ABL1 inhibitors, nelarabine, BCL2 inhibitors
JAK inhibitors, BCL2 inhibitors
Hyperdiploidy with more than 50 chromosomes Near-haploid
Low hypodiploid
iAMP21
t(12;21)(p13;q22) encoding ETV6-RUNX1
ETV6-RUNX1–like t(1;19)(q23;p13)
encoding TCF3-PBX1 t(9;22)(q34;q11.2)
encoding BCR-ABL1 Ph-like
CRLF2 rearranged (IGH-CRLF2; P2RY8- CRLF2)
KMT2A (MLL) rearranged
DUX4 rearranged and ERG deregulated
MEF2D rearranged ZNF384 rearranged PAX5alt
PAX5 P80R
IKZF1 N159Y NUTM1 rearranged
t(17;19)(q22;p13) encoding TCF3-HLF
BCL2/MYC rearranged
T-lineage acute lymphoblastic leukemia
Children >> adults
Children-adults
Children < adults
Older children
Children >> adults
Children > adults
Children-adults
Children << adults
Children < adults
Children < adults
Infants >> children-adults
Children-adults
Children-adults
Children
Children > adults
Children < adults Children-adults Children Children-adults
Children << adults
TAL1 deregulation TLX3 deregulation
HOXA deregulation TLX1 deregulation
LMO2/LYL1 deregulation NKX2-1 deregulation
NUP214-ABL1 with 9q34 amplification
Early T-cell precursor ALL
Children-adults
Children-adults
Children-adults
Children > adults Children-adults
Children-adults Children-adults
Children-adults
FISH: fluorescence in situ hybridization; ALL: acute lymphoblastic leukemia; HDAC: histone deacetylase.
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