Deregulation of <i>FOXF1</i> / <i>FENDRR</i> from t(14;16)(q32;q24) defines a subtype of high-risk lineage ambiguous leukemia
Abstract
Abstract Despite great progress in understanding the genomic basis of immature T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL) and acute leukemias of ambiguous lineage, there are still cases that lack defining genetic markers, complicating risk stratification, and limiting targeted therapeutic options. Recent studies have shown that enhancer hijacking drives oncogene activation in approximately half of T-ALL cases, with the BCL11B (BCL11 transcription factor B) enhancer frequently involved. Here, we describe a subtype of leukemia with a distinct gene-expression signature, and immunophenotype characterized by positivity for immature (CD38), myeloid (CD13), T-lymphoid (cytoplasmic [c]CD3, CD7), and B-lymphoid markers (CD19, CD79a, CD10). This subtype is defined by the t(14;16)(q32;q24) translocation, which places the FOXF1 gene and its antisense long noncoding RNA gene FENDRR under the regulatory control of the BCL11B enhancer, leading to their ectopic transcriptional activation. Common concomitant genetic lesions are loss-of-function alterations of GATA3, CDKN2A/CDKN2B deletion and activating JAK/STAT and NOTCH1 pathway mutations. Patients were predominantly children and adolescents/young adults and experienced poor treatment outcome. High-throughput drug screening of 176 compounds demonstrated efficacy of combined BCL2 apoptosis regulator family proteins and JAK/STAT signaling inhibitors. Additionally, the clinical use of tyrosine kinase inhibitors in some of these patients showed therapeutic efficacy. Collectively, these findings identify BCL11B-enhancer–mediated deregulation of FOXF1/FENDRR as a hallmark of a subtype of high-risk lineage ambiguous leukemia that is potentially amenable to targeted therapeutic intervention.
Article Details
Authors (38)
Danika Di Giacomo
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Petri Pölönen
Valentina Bardelli
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Shunsuke Kimura
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University
Valentina Pierini
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Luca Pagliaro
4Department of Medicine and Surgery, Translational Hematology and Chemogenomics, University of Parma, Parma, Italy
Silvia Arniani
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Yunchao Chang
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Qingsong Gao
2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Lindsey E. Montefiori
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Yiming Wu
Chun Shik Park
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
William C. Wright
Federica Vento
4Department of Medicine and Surgery, Translational Hematology and Chemogenomics, University of Parma, Parma, Italy
Huimei Wei
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Caterina Matteucci
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Shaohua Lei
Wojciech Rosikiewicz
6Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN
Carlotta Nardelli
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Anair Graciela Lema Fernandez
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Anna Østergaard
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Emily A. Backhaus Wagner
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Pradyuamna Baviskar
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Marco Cerrano
7S.C. Ematologia, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza-Presidio Molinette, Turin, Italy
Matteo Leocin
8Hematology Unit, Ospedale dell'Angelo, Venice, Italy
Atsushi Manabe
9Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Shinsuke Hirabayashi
9Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Junko Takita
Daisuke Hasegawa
11Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
Satoshi Miyamoto
11Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
Antonio Macchiarulo
12Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
Jason Xu
David T. Teachey
Giovanni Roti
University of Parma, Parma, Italy
Ilaria Iacobucci
2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Roberta La Starza
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Cristina Mecucci
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Charles G. Mullighan