IGH::FENDRR and specific KRAS mutations define a novel B-ALL molecular subtype with poor chemotherapy response
Abstract
Large scale sequencing efforts have defined up to 27 diagnostic entities in B-ALL, leaving few samples without subtype assignment. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection and holds the potential to identify novel B-ALL subtypes. By analyzing an aggregated set of 4,857 B-ALL patients from three cohorts, we identified a novel group of twenty cases (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=86/4,857; p<0.001) 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 signaling signatures. A gene expression machine learning classifier identified FOXF1/FENDRR cases in two independent cohorts with high accuracy. Patients treated according to GMALL/GRAALL protocols showed very poor chemotherapy response with n=8/13 having induction failure or MRD ≥10-3 and n=8/12 remaining MRD positive after 1st consolidation / salvage. MRD-stratified intensification including blinatumomab (n=10) and/or allogenic stem cell transplantation (n=12) resulted in ongoing molecular remission in 13/16 cases. FOXF1/FENDRR patients represent a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.
Article Details
Authors (28)
Sonja Bendig
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Alina M. Hartmann
Medical Department II, Hematology/Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
Wiebke Wessels
Thomas Beder
Rathana Kim
2Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
Marie Passet
2Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
Qingsong Gao
2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Nadine Wolgast
Medical Department II, Hematology/Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
Johanna M. Horns
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Leonardo Alves Santos
Medical Department II, Hematology/Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
Katharina Iben
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Fabio D. Steffen
Department of Oncology and Children's Research Center, University Children's Hospital, Zurich, Switzerland
Loredana Cantoni
Department of Oncology and Children's Research Center, University Children's Hospital, Zurich, Switzerland
Britta Kehden
Medical Department II, Hematology/Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
Guranda Chitadze
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Axel Künstner
Hauke Busch
Beat Bornhauser
Jean-Pierre Bourquin
Thibaut TL Leguay
Hematology Department, CHU de Bordeaux, Hôpital du Haut-Levêque, Pessac, France
Nicolas Boissel
Nicola Gökbuget
26Department of Medicine II, Hematology/Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
Ilaria Iacobucci
2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Charles G. Mullighan
Emmanuelle Clappier
2Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
Claudia D Baldus
Medical Department II, Hematology/Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
Monika Brüggemann
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Lorenz Bastian