IGH :: FENDRR and specific KRAS mutations define a novel B-ALL molecular subtype with poor chemotherapy response
Year: 2026
Type: article
Study design: Observational Study
Abstract: ABSTRACT: Large-scale sequencing efforts have defined up to 27 diagnostic subtypes in B-cell precursor acute lymphoblastic leukemia (B-ALL), leaving few samples unclassified. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection, enabling identification of novel subtypes. We analyzed 4857 patients with B-ALL from 3 cohorts and identified a group of 20 patients (age, 18-66 years; median, 34 years) characterized by a previously undescribed IGH::FENDRR rearrangement exclusive to this subtype (n = 17/20), KRAS p.A146T/V/P mutations (n = 17/20 vs n = 86/4857; P< .001), and distinct DNA methylation/gene expression profiles, including overexpression of the lncRNA FENDRR and the transcription factor FOXF1 (FOXF1/FENDRR) as well as JAK/STAT and RAS/MAPK signaling signatures. A gene expression machine learning classifier accurately identified FOXF1/FENDRR cases in 2 independent cohorts. Patients treated according to German Multicenter Study Group for Adult ALL (GMALL)/Group for Research in Adult ALL (GRAALL) protocols showed very poor chemotherapy response with 8 of 13 exhibiting induction failure or minimal residual disease (MRD) ≥10-3 and 8 of 12 remaining MRD positive after first consolidation/salvage. Intensification including blinatumomab (n = 10) and/or allogeneic stem cell transplantation (n = 12) resulted in ongoing molecular remission in 13 of 16 patients. FOXF1/FENDRR represents a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.
Source: Blood
Authors: Sonja Bendig, Alina M. Hartmann, Wiebke Wessels, Thomas Beder, Rathana Kim, Marie Passet, Qingsong Gao, Nadine Wolgast, Johanna M. Horns, Leonardo Alves Santos, Katharina Iben, Fabio D. Steffen, Loredana Cantoni, Britta Kehden, Guranda Chitadze, Axel Künstner, Hauke Busch, Beat Bornhauser, Jean-Pierre Bourquin, Thibaut Leguay, Nicolas Boissel, Nicola Gökbuget, Ilaria Iacobucci, Charles G. Mullighan, Emmanuelle Clappier, Claudia D. Baldus, Monika Brüggemann, Lorenz Bastian
Institutions: University Hospital Schleswig-Holstein, Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Louis, Institut de recherche Saint-Louis, St. Jude Children's Research Hospital, University Children's Hospital Zurich, University of Lübeck, Centre Hospitalier Universitaire de Bordeaux, Goethe University Frankfurt
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
Awards: G169511485, G1971263922, Klinisches Wissenschaftlerprogramm für Evolutionäre Medizin, KFO 5010: CATCH ALL Heilungsperspektive für alle Erwachsenen und Kinder mit Akuter Lymphoblastischer Leukämie (ALL), G6289520395, Translating genomic discoveries to improved outcomes for high risk acute leukemia
OpenAlex ID: W7141579508
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