Key genetic alterations in ALL
| Gene . | Alteration . | Frequency . | Pathway and consequences of alteration . | Clinical relevance . | Reference . |
|---|---|---|---|---|---|
| PAX5 | Focal deletions, translocations, and sequence mutations | 30% of B-ALL | Transcription factor required for B-lymphoid development; mutations impair DNA binding and transcriptional activation | Important in leukemogenesis, but not associated with adverse outcome | 3-5 |
| IKZF1 | Focal deletions or sequence mutations | 15% of all pediatric B-ALL cases, including 70%-80% of BCR-ABL1-positive ALL and one-third of high-risk BCR-ABL1-negative B-ALL | Transcription factor required for development of HSC to lymphoid precursor; deletions and mutations result in loss of function or dominant-negative isoforms | Associated with poor outcome | 4, 5, 7, 51, 102 |
| JAK1/2 | Pseudokinase and kinase domain mutations | 18%-35% of DS ALL and 10.7% high-risk BCR-ABL1-negative ALL | Constitutive JAK-STAT activation | Potential for targeting with TKIs that inhibit JAK1/2 | 8, 39, 43 |
| CRLF2 | Rearrangement as IGH-CRLF2 or P2RY8-CRLF2 resulting in overexpression | 5%-16% of pediatric and adult B-ALL and >50% DS ALL; 50% of Ph-like ALL | Associated with mutant JAK in up to 50% of cases; CRLF2 mutations and JAK mutations are cotransforming in cell lines/F3 cells and result in constitutive STAT activation; in high-risk B-ALL, associated with IKZF1 alterations, JAK mutations, and poor outcome | Detected by flow cytometry or molecular assays; potential for targeting with JAK inhibitors | 6, 29, 41, 42, 44 |
| Kinase-activating alterations in Ph-like ALL | Rearrangements of 13 cytokine receptors and tyrosine kinases; sequence mutations of IL7R and FLT; deletions of SH2B3 | 10% childhood B-ALL, up to 30% ALL in adult ALL; associated with Ph-like gene expression profile | Activation of kinase signaling pathways and amenable to TKI therapy | Associated with high-risk features and increased risk of relapse; anecdotal reports of response to TKI therapy | 14, 22, 30, 54 |
| NOTCH1 | Mutations, rarely deletions | >60% T-ALL | Activation of NOTCH1 signaling; mutations in FBXW7 and PTEN also influence NOTCH1 signaling and prognosis | Key pathogenic lesion in T-ALL; direct targeting limited by toxicity; variable associations with outcome | 62 |
| CREBBP | Focal deletion and sequence mutations | 19% of relapsed ALL; also mutated in non-Hodgkin lymphoma | Mutations result in impaired histone acetylation and transcriptional regulation | Mutations selected for at relapse and associated with glucocorticoid resistance | 11, 35 |
| NT5C2 | Focal mutations | Up to 20% relapsed mutation | Mutations in gain of function | Mutations selected at relapse and associated with resistance to thiopurines | 17, 84 |
| TP53 | Deletions and focal mutations | ∼90% of LH ALL, otherwise uncommon in predominant clone at diagnosis | Frequently germline in LH ALL; confer resistance to therapy | Hallmark of LH ALL at diagnosis; associated with disease relapse | 15, 83 |
| Gene . | Alteration . | Frequency . | Pathway and consequences of alteration . | Clinical relevance . | Reference . |
|---|---|---|---|---|---|
| PAX5 | Focal deletions, translocations, and sequence mutations | 30% of B-ALL | Transcription factor required for B-lymphoid development; mutations impair DNA binding and transcriptional activation | Important in leukemogenesis, but not associated with adverse outcome | 3-5 |
| IKZF1 | Focal deletions or sequence mutations | 15% of all pediatric B-ALL cases, including 70%-80% of BCR-ABL1-positive ALL and one-third of high-risk BCR-ABL1-negative B-ALL | Transcription factor required for development of HSC to lymphoid precursor; deletions and mutations result in loss of function or dominant-negative isoforms | Associated with poor outcome | 4, 5, 7, 51, 102 |
| JAK1/2 | Pseudokinase and kinase domain mutations | 18%-35% of DS ALL and 10.7% high-risk BCR-ABL1-negative ALL | Constitutive JAK-STAT activation | Potential for targeting with TKIs that inhibit JAK1/2 | 8, 39, 43 |
| CRLF2 | Rearrangement as IGH-CRLF2 or P2RY8-CRLF2 resulting in overexpression | 5%-16% of pediatric and adult B-ALL and >50% DS ALL; 50% of Ph-like ALL | Associated with mutant JAK in up to 50% of cases; CRLF2 mutations and JAK mutations are cotransforming in cell lines/F3 cells and result in constitutive STAT activation; in high-risk B-ALL, associated with IKZF1 alterations, JAK mutations, and poor outcome | Detected by flow cytometry or molecular assays; potential for targeting with JAK inhibitors | 6, 29, 41, 42, 44 |
| Kinase-activating alterations in Ph-like ALL | Rearrangements of 13 cytokine receptors and tyrosine kinases; sequence mutations of IL7R and FLT; deletions of SH2B3 | 10% childhood B-ALL, up to 30% ALL in adult ALL; associated with Ph-like gene expression profile | Activation of kinase signaling pathways and amenable to TKI therapy | Associated with high-risk features and increased risk of relapse; anecdotal reports of response to TKI therapy | 14, 22, 30, 54 |
| NOTCH1 | Mutations, rarely deletions | >60% T-ALL | Activation of NOTCH1 signaling; mutations in FBXW7 and PTEN also influence NOTCH1 signaling and prognosis | Key pathogenic lesion in T-ALL; direct targeting limited by toxicity; variable associations with outcome | 62 |
| CREBBP | Focal deletion and sequence mutations | 19% of relapsed ALL; also mutated in non-Hodgkin lymphoma | Mutations result in impaired histone acetylation and transcriptional regulation | Mutations selected for at relapse and associated with glucocorticoid resistance | 11, 35 |
| NT5C2 | Focal mutations | Up to 20% relapsed mutation | Mutations in gain of function | Mutations selected at relapse and associated with resistance to thiopurines | 17, 84 |
| TP53 | Deletions and focal mutations | ∼90% of LH ALL, otherwise uncommon in predominant clone at diagnosis | Frequently germline in LH ALL; confer resistance to therapy | Hallmark of LH ALL at diagnosis; associated with disease relapse | 15, 83 |
DS, Down syndrome; HSC, hematopoietic stem cell; NR, none reported.