Table I. Common genetic alterations in childhood ALL.

Note that percentages may total more than 100% due to co-occurrence of genetic lesions. Data are summarized from those delineated in the main text and updated from Tasian et al (2015)

Genetic subtype	Common alterations	Frequency in ALL	Prognosis	Comment
B-ALL
Abnomalities in Chromosome Number
High hyperdiploidy (51-67  chromosomes)		25%	Favourable
Low hyperdiploidy (47-50  chromosomes)		14%	Previously unfavourable, now intermediate
Hypodiploidy (<44 chromosomes)	Near-haploidy (24-31 chromosomes), low- hypodiploidy (32-39 chromosomes)	1-2%	Unfavourable	Association with TP53 mutations, IKZF2 and IKZF3 deletions, and RAS and PI3K pathway mutations
Recurrent Chromosomal Translocations
t(12;21)(p13;q22)	ETV6-RUNX1 (TEL-AML1)	20%	Favourable
t(1;19)(q23;p13.1)	TCF3-PBX1 (E2A-PBX1)	4%	Intermediate
t(17;19)(q22;p13)	TCF3-HLF	<0.5%	Unfavourable
KMT2A (MLL) rearrangements		5-6%	Unfavourable (infants), intermediate (non- infants)	Highest frequency in younger infants (80%); associated with FLT3 overexpression and epigenetic dysregulation
t(1;11)(q21;q23)	KMT2A-MLLT11		Less unfavourable	Rare
t(4;11)(q21;q23)	KMT2A-AFF1 (AF4)		Particularly unfavourable	Comprises 50% of infant KMT2A- rearranged ALL
t(9;11)(p22;q23)	KMT2A-MLLT3 (AF9)			Comprises 15% of infant KMT2A- rearranged ALL
t(10;11)(p12;q23)	KMT2A-MLLT10 (AF10)			Comprises 5% of infant KMT2A- rearranged ALL
t(11;19)(q23;p13.3)	KMT2A-MLLT1 (ENL)			Comprises 20-25% of infant KMT2A- rearranged ALL
Other fusion partners
t(9;22)(q34;q11.2)	BCR-ABL1	3-5%	Unfavourable prior to TKI therapy, intermediate with TKI therapy?	Associated with IKZF1 deletions
Other
Ph-like	IGH-CRLF2, P2RY8- CRLF2	7-8%	Unfavourable	50% of Ph-like; associated with JAK1 and JAK2 mutations, CDKN2A/B deletions, IKZF1 deletions; increasing incidence with older age; possibly targetable with TKIs
	ABL1, ABL2, CSF1R, PDGFRB rearrangements	5-6%	Unfavourable	10-20% of Ph-like; potentially targetable with TKIs
	EPOR, JAK2 rearrangements	2%	Unfavourable	10% of Ph-like; potentially targetable with TKIs
Trisomy 21-associated ALL	P2RY8-CRLF2, JAK2 mutations	50-60% of DS-ALL	Intermediate
iAMP21	Multiple copies of RUNX1	2%	Unfavourable	Rare rob(15;21)(q10;q10)c associated with greatly increased risk of iAMP21 ALL
DUX4 rearrangements	IGH-DUX4, ERG-DUX4	3-7%	Favourable	Associated with IKZF1 deletions, ERG dysregulation, aberrant CD2 expression
MEF2D rearrangements	MEF2D-BCL9, MEF2D- HNRNPUL1	3-6%	Unfavourable	Multiple fusion partners, possible role for epigenetic therapies
ZNF384 rearrangements	EP300-ZNF384	4%	Intermediate	Multiple fusion partners, possible role for JAK inhibitors
T-ALL
Recurrent Chromosomal Translocations
t(10;14)(q24;q11)	TLX1 (HOX11) fusions	5-10% of T- ALL	Favourable	Associated with PHF6 mutations
t(7;19)(q34;p13)	LYL1 fusions	10% of T- ALL	Unfavourable
t(1;14)(p32;q11), t(1;7)(p32;q34),  t(11;14)(p15;q11),  t(11;14)(p13;q11)	TAL1, LMO1, LMO2 fusions	50-60% of T- ALL	Unfavourable	Associated with PHF6 mutations
t(11;14)(p15;q11), t(5;14)(q35;q32)	TLX3 (HOX11L2) fusions	20-25% of T- ALL	Unfavourable (some studies), intermediate (some studies), favourable (some studies)	Associated with PHF6 mutations
t(8;14)(q24;q11)	TRA-MYC, TRC-MYC	1% of T-ALL	Probably unfavourable	Associated with MYC activation and aggressive phenotype
7p15 translocations	HOXA10, HOXA9 overexpression	3% of T-ALL	Unfavourable
KMT2A (11q23) rearrangements	KMT2A-AFF1, KMT2A- MLLT1	5% of T-ALL	Possibly favourable
t(10;11)(p13;q21)	PICALM-MLLT10 (CALM- AF10)	5-10% of T- ALL	Unfavourable (some studies), intermediate (other studies)	Associated with EZH2 alterations
t(9;14)(q34;q32)	NUP214-ABL1	5-15% of T- ALL	Unfavourable (some studies), intermediate (other studies)	Associated with TLX1 and TLX3 (HOX11L2) overexpression
Other
NOTCH1 mutations		50-60% of T- ALL	Favourable	Associated with CDKN2A and FBXW7 deletions
ETP		10-15% of T- ALL	Unfavourable (some studies), intermediate (other studies)	Associated with Ras pathway mutations; characteristic immunophenotype (CD1a-, CD8-, CD5- or CD5-dim with co- expression of myeloid or stem cell markers)
FBXW7 mutation		15% of T- ALL		Associated with NOTCH1 activation via impairment of proteasomal degradation of NOTCH1
Other T-ALL		6% of T-ALL
Relapsed ALL				Associated with chemotherapy resistance
	CREBBP mutation	20% of relapsed ALL		Probably confers resistance to glucocorticoids
	NT5C2 mutation	20% of relapsed ALL		Probably confers resistance to nucleoside analogues
	PRPS1 mutation	7% of relapsed ALL		Probably confers resistance to nucleoside analogues
	MSH6 deletion
	NR3C1 deletion
	SETD2 mutation	12% of relapsed ALL		Suggests possible role for epigenetic therapies
	KDM6A mutation
	KMT2D (MLL2) mutation
	RAS pathway mutations	30-50% of relapsed ALL

ALL = acute lymphoblastic leukaemia; B-ALL = B cell acute lymphoblastic leukaemia; DS-ALL = Down syndrome-associated ALL; iAMP21 = intrachromosomal amplification of chromosome 21; T-ALL = T cell acute lymphoblastic leukaemia; TKI = tyrosine kinase inhibitor.