Novel genomic alterations with potential prognostic or therapeutic relevance
| Gene . | Alteration . | Frequency . | Pathway and consequences of alteration . | Clinical relevance . | References . |
|---|---|---|---|---|---|
| PAX5 | Focal deletions, translocations, sequence mutations | 31.7% of precursor B-cell ALL | Transcription factor required for B-lymphoid development Mutations impair DNA binding and transcriptional activation | Role in pathogenesis of precursor B-ALL; not related to outcome | 31,–33 |
| IKZF1 | Focal deletions or sequence mutations | 15% of all pediatric precursor B-cell ALL cases | Transcription factor required for lymphoid development Deletions and mutations result in loss of function or dominant negative isoforms | 31 | |
| > 80% BCR-ABL1 ALL and 66% chronic myeloid leukemia in lymphoid blast crisis | Associated with poor outcome | 32,34,35 | |||
| One-third of high-risk BCR-ABL1 negative ALL | 3-fold increased risk of relapse | 27,28,36 | |||
| Inherited variants | Increased risk of ALL | 37,38 | |||
| JAK1/2 | Pseudokinase and kinase domain mutations | 18%-35% Down syndrome ALL | Constitutive JAK-STAT activation | May be responsive to JAK inhibitors | 39,40,–42 |
| 10.7% high-risk BCR-ABL1 negative ALL | 39 | ||||
| CRLF2 | Rearrangement as IGH@-CRLF2 or P2RY8-CRLF2 resulting in overexpression | 5%-16% pediatric and adult precursor B-cell ALL, and > 50% Down syndrome-ALL | Associated with mutant JAK in up to 50% of cases | 21,22,44,45 | |
| 14% pediatric high-risk ALL | Associated with IKZF1 alteration and JAK mutations | Associated with poor outcome | 23,24 | ||
| CREBBP | Focal deletion and sequence mutations | 19% of relapsed ALL; commonly acquired at relapse | Mutations result in impaired histone acetylation and transcriptional regulation | Associated with glucocorticoid resistance | 45,46 |
| TP53 | Deletions and sequence mutations | Up to 3% precursor B-cell ALL, commonly acquired at relapse | Loss of function or dominant negative | Associated with poor outcome | 47 |
| Gene . | Alteration . | Frequency . | Pathway and consequences of alteration . | Clinical relevance . | References . |
|---|---|---|---|---|---|
| PAX5 | Focal deletions, translocations, sequence mutations | 31.7% of precursor B-cell ALL | Transcription factor required for B-lymphoid development Mutations impair DNA binding and transcriptional activation | Role in pathogenesis of precursor B-ALL; not related to outcome | 31,–33 |
| IKZF1 | Focal deletions or sequence mutations | 15% of all pediatric precursor B-cell ALL cases | Transcription factor required for lymphoid development Deletions and mutations result in loss of function or dominant negative isoforms | 31 | |
| > 80% BCR-ABL1 ALL and 66% chronic myeloid leukemia in lymphoid blast crisis | Associated with poor outcome | 32,34,35 | |||
| One-third of high-risk BCR-ABL1 negative ALL | 3-fold increased risk of relapse | 27,28,36 | |||
| Inherited variants | Increased risk of ALL | 37,38 | |||
| JAK1/2 | Pseudokinase and kinase domain mutations | 18%-35% Down syndrome ALL | Constitutive JAK-STAT activation | May be responsive to JAK inhibitors | 39,40,–42 |
| 10.7% high-risk BCR-ABL1 negative ALL | 39 | ||||
| CRLF2 | Rearrangement as IGH@-CRLF2 or P2RY8-CRLF2 resulting in overexpression | 5%-16% pediatric and adult precursor B-cell ALL, and > 50% Down syndrome-ALL | Associated with mutant JAK in up to 50% of cases | 21,22,44,45 | |
| 14% pediatric high-risk ALL | Associated with IKZF1 alteration and JAK mutations | Associated with poor outcome | 23,24 | ||
| CREBBP | Focal deletion and sequence mutations | 19% of relapsed ALL; commonly acquired at relapse | Mutations result in impaired histone acetylation and transcriptional regulation | Associated with glucocorticoid resistance | 45,46 |
| TP53 | Deletions and sequence mutations | Up to 3% precursor B-cell ALL, commonly acquired at relapse | Loss of function or dominant negative | Associated with poor outcome | 47 |