New entities in B-ALL defined by structural alterations
| Subtype . | Frequency . | Prognosis . | Diagnostic approach . | Partner genes . | Immunophenotype . | Comment . | References . |
|---|---|---|---|---|---|---|---|
| B-ALL with MYC rearrangement | 2-5%, higher in adults and AYA) | Poor | FISH MYC/BCL2/BCL6; Ig V(H) mutational status | IGH | TdT+CD34-CD20+/−; may be SIg+ | May have BCL2/ BCL6 rearrangements | 217,218,241 |
| B-ALL with DUX4 rearrangement | 5-10%, highest in AYA and adult | Excellent | WTS,* IHC for DUX4 overexpression | Enhancers, most commonly IGH | CD371+; CD2+ | Common ERG and IKZF1 deletions | 221-225 |
| B-ALL with MEF2D rearrangement | 3-5% | Poor | WTS; FISH MEF2D | BCL9, HNRNPUL1 | CD10-/dim; CD38+; cu+ | 226,227 | |
| B-ALL with ZNF384 or ZNF362 rearrangement | 5-10%, higher inAYA | Variable | WTS; FISH possible | EP300 (most common and good prognosis), TCF3, TAF15, CREBBP | CD10-/dim; myeloid antigen + | ∼50% of B/My MPAL in children, but not adults; FLT3 overexpression | 229-232 |
| B-ALL with NUTM1 rearrangement | 2% or less; rare in adults, mostly in infants lacking KMT2A rearrangements | Good | FISH NUTM1; WTS; NUTM1 overexpression (WTS, RT-PCR, IHC) | ACIN1, ZNF618, BRD9, IKZF1, CUX1 | CD10-/dim; expression of myeloid markers (CD13/CD15/CD33) | Common overexpression of HOXA9 | 234,235 |
| B-ALL/LL with HLF rearrangement | <<1% children | Very poor | WTS; FISH HLF | TCF3; TCF4 | Unknown | May respond to anti-CD19 therapy | 237 |
| CDX2/UBTF | <1%; higher in AYA and females | Poor | RT PCR, WTS | UBTF::ATXN7L3 by cryptic deletion of 17q21.31; high expression of CDX2 by deletion FLT3/PAN3 at 13q12.2) | CD10 negative and cytoplasmic IgM positive | 238-240 | |
| B-ALL/LL with mutated IKZF1 N159Y | <1% all ages | Intermediate | Exome/gene panel sequencing | N.A. | Unknown | Distinct gene expression profile; gain of chromosome 21 in 75% of cases | 241,244 |
| B-ALL/LL with mutated PAX5 P80R | 2-5% higher in adult | Intermediate, good in adults | Exome/gene panel sequencing | N.A. | Biallelic PAX5 alterations from deletion or LOF mutation of second allele; CDKN2A loss; JAK and RAS signaling gene mutations | 241,242,263 |
| Subtype . | Frequency . | Prognosis . | Diagnostic approach . | Partner genes . | Immunophenotype . | Comment . | References . |
|---|---|---|---|---|---|---|---|
| B-ALL with MYC rearrangement | 2-5%, higher in adults and AYA) | Poor | FISH MYC/BCL2/BCL6; Ig V(H) mutational status | IGH | TdT+CD34-CD20+/−; may be SIg+ | May have BCL2/ BCL6 rearrangements | 217,218,241 |
| B-ALL with DUX4 rearrangement | 5-10%, highest in AYA and adult | Excellent | WTS,* IHC for DUX4 overexpression | Enhancers, most commonly IGH | CD371+; CD2+ | Common ERG and IKZF1 deletions | 221-225 |
| B-ALL with MEF2D rearrangement | 3-5% | Poor | WTS; FISH MEF2D | BCL9, HNRNPUL1 | CD10-/dim; CD38+; cu+ | 226,227 | |
| B-ALL with ZNF384 or ZNF362 rearrangement | 5-10%, higher inAYA | Variable | WTS; FISH possible | EP300 (most common and good prognosis), TCF3, TAF15, CREBBP | CD10-/dim; myeloid antigen + | ∼50% of B/My MPAL in children, but not adults; FLT3 overexpression | 229-232 |
| B-ALL with NUTM1 rearrangement | 2% or less; rare in adults, mostly in infants lacking KMT2A rearrangements | Good | FISH NUTM1; WTS; NUTM1 overexpression (WTS, RT-PCR, IHC) | ACIN1, ZNF618, BRD9, IKZF1, CUX1 | CD10-/dim; expression of myeloid markers (CD13/CD15/CD33) | Common overexpression of HOXA9 | 234,235 |
| B-ALL/LL with HLF rearrangement | <<1% children | Very poor | WTS; FISH HLF | TCF3; TCF4 | Unknown | May respond to anti-CD19 therapy | 237 |
| CDX2/UBTF | <1%; higher in AYA and females | Poor | RT PCR, WTS | UBTF::ATXN7L3 by cryptic deletion of 17q21.31; high expression of CDX2 by deletion FLT3/PAN3 at 13q12.2) | CD10 negative and cytoplasmic IgM positive | 238-240 | |
| B-ALL/LL with mutated IKZF1 N159Y | <1% all ages | Intermediate | Exome/gene panel sequencing | N.A. | Unknown | Distinct gene expression profile; gain of chromosome 21 in 75% of cases | 241,244 |
| B-ALL/LL with mutated PAX5 P80R | 2-5% higher in adult | Intermediate, good in adults | Exome/gene panel sequencing | N.A. | Biallelic PAX5 alterations from deletion or LOF mutation of second allele; CDKN2A loss; JAK and RAS signaling gene mutations | 241,242,263 |
AYA, adolescents and young adults; WTS, whole transcriptome sequencing
Whole transcriptome sequencing may not detect DUX4 rearrangements in all cases due to repetitive genomic features at both DUX4 and IGH loci.