Clinical Report: CEBP-Altered B-ALL Across Ages: Two Distinct Transcriptomic Profiles

Overview

Whole-transcriptome sequencing of 24 CEBP-altered B-ALL cases from pediatric, adolescent and young adult, and adult patients separated the cases into two transcriptomic clusters. Their molecular features broadly recapitulated the CEBP/ZEB2 and CEBPalt subtypes reported by Kim et al., while the age and sex distributions did not differ significantly between clusters in this cohort.

Background

The International Consensus Classification provisionally defines a B-ALL entity involving ZEB2 p.H1038R and/or IGH::CEBPE. Prior integrated genomic and transcriptomic analyses identified distinct CEBP- and ZEB2-associated subtypes with different cooperating lesions and clinical features. The present study examined CEBP-altered B-ALL across pediatric, AYA, and adult age groups using whole-transcriptome sequencing. The authors note that IGH rearrangements can be difficult to detect with established analytical methods, potentially limiting recognition of some cases.

Data Highlights

Key Findings

• Unbiased whole-transcriptome analysis separated 24 CEBP-altered cases into two clusters without whole-genome or whole-exome sequencing, optical genome mapping, or ATAC-seq.
• Cluster A featured concurrent ZEB2 p.H1038R and NRAS mutations and most closely aligned with the CEBP/ZEB2 subtype described by Kim et al.
• Cluster B was characterized by FLT3 mutations and frequent IKZF1 deletion, aligning with the CEBPalt subtype; it also showed a higher overall burden of genomic complexity.
• CDKN2A deletions and NRAS mutations were significantly more frequent in Cluster A (P = 0.02 and P = 0.0013, respectively).
• CEBPE rearrangements occurred only in Cluster A, whereas CEBPD rearrangements occurred only in Cluster B.
• The clusters differed in B-cell developmental-stage enrichment: Cluster B showed enrichment for pre-B I cells, while Cluster A contained more pre-B II Small or Immature B cells. Cluster B also showed FLT3 activation and higher FLT3 expression.
• Unlike the age- and sex-related associations reported by Kim et al., this non-consecutive cohort showed no significant age-group or sex differences between clusters. The authors call for larger independent cohorts to assess this discrepancy.

Clinical Implications

The authors report that the Recovering IGH Fusion Transcripts (RIGHT) workflow, together with examination of regions flanking CEBP genes, enabled detection of CEBP rearrangements in 19 of 24 cases through transcriptomic sequencing. They state that whole-genome sequencing and optical genome mapping remain important for identifying noncoding regulatory alterations and cryptic structural variants that may not produce detectable fusion transcripts. The authors note that distinguishing recognition of the disease entity from resolution of its underlying genomic mechanisms has relevance for diagnostic classification.

Conclusion

Across a cohort spanning pediatric, AYA, and adult patients, transcriptomic analysis identified two CEBP-altered B-ALL profiles with molecular features concordant with previously described CEBP/ZEB2-associated and CEBPalt groups. The findings support further evaluation of these profiles across larger cohorts and with complementary genomic methods.

Related Resources & Content

1. Kim et al., PubMed, 2026 — CEBP and ZEB2 alterations define three distinct subtypes of B-cell acute lymphoblastic leukemia
2. International Consensus Classification, 2022 — International Consensus Classification of Acute Lymphoblastic Leukemia/Lymphoma
3. ASCO Publications — Defining APOBEC-like signature in diffuse large B-cell lymphoma and demonstration of distinct transcriptomic profile.
4. ASCO Publications — Differential Gene Expression Patterns and Interaction Networks in BCR-ABL–Positive and –Negative Adult Acute Lymphoblastic Leukemias
5. ASCO Publications — Defining APOBEC-like signature in diffuse large B-cell lymphoma and demonstration of distinct transcriptomic profile.
6. ASCO Publications — Identification of a new subgroup of adult acute T-lymphoblastic leukemia (T-ALL) with a very favorable outcome using low ERG and BAALC expression
7. CEBP and ZEB2 alterations define three distinct subtypes of B-cell acute lymphoblastic leukemia
8. International Consensus Classification of Acute Lymphoblastic Leukemia/Lymphoma
9. American Society of Hematology 2026 guidelines for frontline management of acute lymphoblastic leukemia in adolescents and young adults - PMC