IGH::FENDRR and specific KRAS mutations define a novel B-ALL molecular subtype with poor chemotherapy response

Area of Science:

• Hematology
• Genomics
• Molecular Biology

Background:

• Current B-acute lymphoblastic leukemia (B-ALL) classification identifies numerous subtypes, yet some cases remain unassigned.
• Advanced genomic and transcriptomic profiling can uncover novel B-ALL subtypes.

Purpose of the Study:

• To identify and characterize novel subtypes of B-ALL using large-scale patient data.
• To investigate the clinical features and treatment response of a newly identified B-ALL subtype.

Main Methods:

• Analysis of aggregated genomic and transcriptomic data from 4,857 B-ALL patients across three cohorts.
• Identification of novel genetic rearrangements (IGH::FENDRR) and mutations (KRAS p.A146T/V/P).
• DNA methylation and gene expression profiling, including machine learning classification.

Main Results:

• A novel B-ALL subtype, 'FOXF1/FENDRR', was identified in 20 adult patients (median age 34 years).
• This subtype is characterized by IGH::FENDRR rearrangement (17/20), KRAS mutations (17/20), and overexpression of FENDRR and FOXF1.
• Patients showed poor response to standard chemotherapy (8/13 induction failure or MRD ≥10-3) but improved outcomes with intensified MRD-stratified treatment (13/16 ongoing remission).

Conclusions:

• FOXF1/FENDRR represents a distinct adult B-ALL subtype with unique molecular features.
• This subtype exhibits resistance to conventional chemotherapy.
• Early immunotherapeutic or targeted interventions may improve outcomes for FOXF1/FENDRR B-ALL patients.